Synthesis of enantiopure ethyl deoxymonate B from allylic sulfinyl dihydropyrans

Article abstract of DOI:10.1016/j.tetlet.2008.04.107

A completely stereoselective dihydroxylation of a dihydropyranol and a cross-metathesis in the presence of a free homoallylic hydroxyl group are the key steps of a synthesis of enantiopure ethyl deoxymonate B from a sulfinyl dienol.

Full text of DOI:10.1016/j.tetlet.2008.04.107

Tetrahedron Letters 49 (2008) 4167–4169
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Synthesis of enantiopure ethyl deoxymonate B from allylic
sulfinyl dihydropyrans
*
Roberto Fernández de la Pradilla , Nadia Lwoff
Instituto de Química Orgánica, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A completely stereoselective dihydroxylation of a dihydropyranol and a cross-metathesis in the presence
of a free homoallylic hydroxyl group are the key steps of a synthesis of enantiopure ethyl deoxymonate B
from a sulfinyl dienol.
Received 27 March 2008
Accepted 18 April 2008
Available online 23 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Pseudomonic Acids
Allylic Sulfoxides
Sigmatropic rearrangement
Stereoselective dihydroxylation
The base-promoted cyclization of hydroxy sulfinyl dienes I
(Scheme 1) affords 2,3-trans sulfinyl dihydropyrans with high
selectivity.1 In most cases, these allylic sulfoxides II are unusually
stable and finding suitable conditions to carry out a synthetically
useful sulfoxide sulfenate [2,3]-sigmatropic rearrangement in good
yields required considerable experimentation.2 The use of DABCO
in toluene at 70 °C gave consistently high yields of the desired
allylic alcohols III and this encouraged us to pursue synthetic
applications of the methodology.3,4 Scheme 1 gathers our prelimin-
ary results on the osmium-catalyzed dihydroxylation of model
trans allylic alcohol 2, readily available from sulfinyl dihydropyran
1, and its cis diastereomer 5, prepared from 2 by a Mitsunobu pro-
tocol. The dihydroxylation of trans allylic alcohol 2 under standard
conditions afforded a 60:40 mixture of triols 3 and 4.5 In contrast,
the dihydroxylation of cis allylic alcohol 5 led to triol 6 as a single
isomer and in good yield. These results encouraged us to address
the application of our methodology to the synthesis of pseudomon-
ic acid B or related compounds (Scheme 2), with a substitution
pattern at the tetrahydropyran ring that resembles that of triol 6
(Scheme 1).
O
S
O
S
H
HO
-Tol Base
p
-Tol Thiophile
OH
p
OH
R
O
II
R
O
III
R
I
O
OH
H
S
HO
HO
OH HO
OH
-Tol
p
i
ii
+
O
-Bu
n
O
-Bu
O
-Bu
O
-Bu
n
n
n
1
2
3 (60)
4
(40)
13
15
HO
iii
11
OH
10
OH
O
HO
HO
OH
-Bu
8
OH
O
iv
-Bu
R
O
O
n
n
16
O
5
5
6
5'
1
CO2H
Scheme 1. Dihydroxylation of dihydropyranyl allylic alcohols. Reagents and con-
ditions: (i) DABCO, toluene, 70 °C, 91%. (ii) OsO4, Me3NOꢀ2H2O, rt, 67%. (iii) (a) PPh3,
p-nitrobenzoic acid, DIAD, THF, rt; (b) K2CO3, MeOH, rt, 71%. (iv) OsO4, Me3NOꢀ
2H2O, rt, 82%.
O
4'
7 Pseudomonic Acid A: R = H
8
9
Pseudomonic Acid B: R = OH
Pseudomonic Acid C:R = H, C-10/C-11 -alkene
E
10
Pseudomonic Acid D: R = H, C-4'/C-5' -alkene
E
* Corresponding author. Tel.: +34 91 562 29 00; fax: +34 91 564 48 53.
E-mail address: iqofp19@iqog.csic.es (R. Fernández de la Pradilla).
Scheme 2. Structure of pseudomonic acids.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.107

4168
R. Fernández de la Pradilla, N. Lwoff / Tetrahedron Letters 49 (2008) 4167–4169
The pseudomonic acids are a family of C-glycopyranosides pro-
O
O
S
O
S
-Tol
p
S
duced by a strain of Pseudomonas fluorescens, that present a potent
antibiotic activity against gram-positive aerobic bacteria.6 Pseudo-
monic acid A 7 is clinically used as a topical antibacterial (Bactro-
ban). This potent activity and their challenging structure have
attracted the interest of many groups and this has led to many syn-
thetic approaches over the last two decades.7 All four pseudomonic
acids are structurally related presenting an a-cis-disubstituted tet-
rahydropyran ring at C-5 and C-8 positions, as well as b-cis hydro-
xyl groups at C-6 and C-7. Pseudomonic acid B presents an
additional oxygenated center at C-8 (Scheme 2), and in pseudo-
monic acid C the C-10/C-11 oxirane is replaced by an E alkene.
Pseudomonic acid D possesses the same general structure as
pseudomonic acid A, except for C-40/C-50 E double bond. The crea-
tion of the key tetrahydropyran core has been pursued by different
strategies, such as the use of carbohydrates, Diels–Alder processes
or from acyclic precursors. The new stereocenters have been estab-
lished by a variety of approaches such as Claisen rearrangements,
Pd-catalyzed alkylations, or radical processes. The a-cis side chains
at C-5 and C-8 have been homologated using several methodolo-
gies, including Wittig and Julia processes and cross-metathesis
reactions.
Bu3Sn
-Tol
-Tol
p
p
i
ii
iii
+
Bu3Sn
OH
OP
OP
OP
OP
13
F
12
14b
14a
(14)
(86)
iv
P = TBDPS
OH
O
S
O
H
O
S
16
I
S
SnBu3
-Tol
p
-Tol
p
-Tol
p
v
vi
O
OH
17
OP
OP
OP
18
15
Scheme 4. Synthesis of sulfinyl dihydropyran 18. Reagents and conditions: (i) T-
BDPSCl, imidazole, DMAP, CH2Cl2, 0 °C to rt, 77%. (ii) (a) EtMgBr, Et2O; (b) (–)-
menthyl p-toluenesulfinate, toluene, ꢁ20 °C, 99%. (iii) Bu3SnH, Pd(PPh3)4, toluene
ꢁ78 °C to rt, 100%. (iv) I2, CH2Cl2, rt, 82%. (v) 16, Ph3As, BHT, Pd2(dba)3ꢀCHCl3, THF,
rt, 99%. (vi) LDA, THF, ꢁ78 °C to rt, 100%.
LDA afforded 2,3-trans sulfinyl dihydropyran 18 as a single isomer
in excellent yield. Thus, the pyran core of the target was built with
the appropriate substitution and absolute configuration at C-5.9
2,3-Sigmatropic rearrangement of allylic sulfoxide 18 afforded
trans allylic alcohol 19 as a single isomer (Scheme 5). Our prelimin-
ary studies on the dihydroxylation of model substrates indicated
that the highest selectivity was obtained for cis-disubstituted dihy-
dropyrans. Thus, the allylic alcohol was inverted by a Mitsunobu
protocol, via p-nitrobenzoate 20, to produce cis alcohol 21. As ex-
pected dihydroxylation with osmium tetroxide afforded triol 22
as the sole product, and the cis diol was protected as a cyclohexy-
lidene ketal obtaining 23.
Alcohol 23 was oxidized to ketone 24 with PCC, and addition of
allylmagnesium bromide to the ketone afforded tertiary alcohol 25
exclusively (Scheme 5).8b Deprotection of the secondary alcohol on
the side chain at C-5 resulted quite slow and led to diol 26 which
was oxidized, to produce ketone 27 as a single product that
There are comparatively few synthetic approaches that address
incorporation of the C-8 hydroxyl group for the preparation of
pseudomonic acid B and related compounds.8 Our retrosynthetic
analysis for ethyl deoxymonate B, 11, is outlined in Scheme 3
and entails a key cross-metathesis step to homologate the side
chain at C-8 of late intermediate A and a Horner-Wadsworth-Em-
mons reaction to build the C-5 side chain. This cross-metathesis in
the presence of a free hydroxyl group at C-8, inspired by the work
of Markó,7g was considered a challenging but interesting solution
to install the side chain. The precursor of intermediate A would
be allylic alcohol B, resulting from the [2,3]-sigmatropic rearrange-
ment of allylic sulfoxide C. Sulfinyl dihydropyran C would result
from the base-mediated cyclization of dienyl sulfoxide D, that
could be prepared from 4-pentyn-2-ol F via iodo vinyl sulfoxide
E by a Stille coupling process with the required hydroxy vinyl
stannane.
Our synthetic efforts toward ethyl deoxymonate B 11, started
from commercially available 4-pentyn-2-ol F (Scheme 4). Protec-
tion of (rac)-4-pentyn-2-ol with TBDPSCl, and reaction of the pro-
tected alkyne 12 with EtMgBr and (–)-menthyl p-toluenesulfinate
led to alkynyl sulfoxide 13 that afforded an 86:14 mixture of
regioisomers 14a and 14b by Pd-catalyzed hydrostannylation.
Tin–iodine exchange on 14a led to vinyl iodide 15 that was submit-
ted to a Stille coupling with hydroxy vinyl stannane 16 to give sul-
finyl diene 17 in excellent yield. Base-promoted cyclization with
O
S
OH
H
HO
HO
HO
OH
-Tol
p
i
ii
iii
O
O
O
O
18
19
21
22
OP
OP
OP
OP
iv
O2N
P= TBDPS
O
O
13
15
HO
O
O
HO
R
O
11
R
10
O
OH
O
O
20
8
OH
O
O
HO
OP
23
OP
OP
HO
HO
16
v
O
O
O
5
O
OP
11
A
B
O
O
O
O
1
O
O
O
OEt
2,3-sigmatropic
rearrangement
vii
vi
HO
HO
O
S
O
S
O
S
O
25
O
24
I
26
-Tol
-Tol
-Tol
p
p
p
OH
OP
OH
O
Base mediated
cyclization
Stille
Scheme 5. Reagents and conditions: (i) DABCO, toluene, 70 °C, 96%. (ii) (a) PPh3,
p-nitrobenzoic acid, DIAD, THF, rt, 84%; (b) K2CO3, MeOH, rt, 94%. (iii) OsO4,
Me3NOꢀ2H2O, acetone:H2O (9:1), rt, 96%. (iv) Cyclohexanone, p-TsOH, toluene, rt,
86%. (v) PCC, 4 Å MS, CH2Cl2, rt, 72%. (vi) allylMgBr, THF, ꢁ30 °C to rt, 70%. (vii)
TBAF, THF-DMF (8:2), 0 °C to rt, 72%, 6% recovered starting material.
OP
OP
OP
OH
F
E
D
C
Scheme 3. Retrosynthetic analysis for ethyl deoxymonate B, 11.

R. Fernández de la Pradilla, N. Lwoff / Tetrahedron Letters 49 (2008) 4167–4169
4169
In summary, readily available enantiopure allylic sulfinyl dihy-
dropyrans have been transformed smoothly into allylic dihydro-
O
O
pyranols that undergo
a highly selective osmium-catalyzed
O
O
dihydroxylation in some cases. This methodology has been applied
to a synthesis of ethyl deoxymonate B that features a homologation
of the C-8 side chain by a cross-metathesis of a homoallylic free
alcohol fragment.
i
ii
HO
26
HO
OTES
29
O
O
28
27
O
CO2Et
iii
Acknowledgements
This research was supported by DGI MEC (CTQ2006-04522/
BQU) and CM (S-SAL-0249-2006). We thank JANSSEN-CILAG for
generous additional support and MEC for a doctoral fellowship to
NL. We are grateful to Dr. J. L. Chiara (IQOG, CSIC) for fruitful
discussions.
HO
TESO
iv
OH
O
OH
O
HO
HO
O
O
11
30
References and notes
CO2Et
CO2Et
1. Fernández de la Pradilla, R.; Tortosa, M. Org. Lett. 2004, 6, 2157–2160.
2. (a) Rayner, D. R.; Miller, E. G.; Bickart, P.; Gordon, A. J.; Mislow, K. J. Am. Chem.
Soc. 1966, 88, 3138–3139; (b) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.;
Mislow, K. J. Am. Chem. Soc. 1968, 90, 4869–4876; (c) Braverman, S.; Stabinsky,
Y. J. Chem. Soc., Chem. Commun. 1967, 270; (d) Evans, D. A.; Andrews, G. C.;
Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956–4957.
Scheme 6. Synthesis of ethyl deoxymonate B 11. Reagents and conditions: (i) PCC,
4 Å MS, CH2Cl2, rt, 86%. (ii) NaH, (EtO)2P(O)CH2CO2Et, THF, ꢁ70 °C to rt, 34%, 60%
recovered starting material. (iii) 30, Grubbs second generation catalyst, toluene,
55 °C, 66%. (iv) DOWEX, MeOH, rt, 80%.
3. A full account of this study will be published elsewhere.
4. For an application to the formal synthesis of ent-dysiherbaine, see: Fernández
de la Pradilla, R.; Lwoff, N.; Viso, A. Tetrahedron Lett. 2007, 48, 8141–8144.
5. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973–1976.
6. (a) Badder, C.; Garre, C. Corresp.-Bl. Sweiz. Aerzte 1887, 17, 385; (b) Fuller, A. T.;
Mellows, G.; Woolford, M.; Banks, G. T.; Barrow, K. D.; Chain, E. B. Nature 1971,
234, 416–417.
7. For a review see: (a) Class, Y. J.; DeShong, P. Chem. Rev. 1995, 95, 1843–1857.
and references therein; For syntheses and synthetic approaches see: (b) Balog,
A.; Yu, M. S.; Curran, D. P. Synth. Commun. 1996, 26, 935–944; (c) Khan, N.; Xiao,
H. Y.; Zhang, B.; Cheng, X. H.; Mootoo, D. R. Tetrahedron 1999, 55, 8303–8312;
(d) McKay, C.; Simpson, T. J.; Willis, C. L.; Forrest, A. K.; O’Hanlon, P. J. Chem.
Commun. 2000, 1109–1110; (e) Sugawara, K.; Imanishi, Y.; Hashiyama, T.
Tetrahedron: Asymmetry 2000, 11, 4529–4535; (f) Taniguchi, T.; Ogasawara, K.
Tetrahedron Lett. 2001, 42, 3359–3361; (g) van Innis, L.; Plancher, J. M.; Markó,
I. E. Org. Lett. 2006, 8, 6111–6114.
8. (a) Schönenberger, B.; Summermatter, W.; Ganter, C. Helv. Chim. Acta 1982, 65,
2333–2337; (b) Kozikowski, A. P.; Sorgi, K. L. Tetrahedron Lett. 1984, 25, 2085–
2088; (c) Honda, T.; Kimura, N. Org. Lett. 2002, 4, 4567–4570.
9. Since our synthetic plan included the oxidation of the secondary alcohol of the
C-5 side chain, the isomers were not separated and all products were
characterized as equimolar mixtures of diastereoisomers before oxidation.
10. We had observed partial migration of the ketal protecting group upon standing
when an isopropylidene derivative was used. A full account of these results will
be described in due time.
appeared to be stable to ketal migration (Scheme 6).10 The Wittig
reaction of 27 with the sodium anion of triethyl phosphonoacetate
afforded 28 as an 80:20 mixture of E/Z isomers11 that was used as a
mixture in the next step. These results could probably be improved
with a thorough study of the conditions for this step, to obtain
higher yield and selectivity. Homologation of the C-8 side chain
was carried out using the same conditions described by Markó et
al. for a related system lacking the extra hydroxyl group at the
homoallylic position.7g To our delight, the cross-metathesis of 28
and fragment 29, prepared in four steps from ethyl (S)-3-hydroxy-
butyrate,12 afforded 30 as an E/Z mixture, with the E isomer as the
major product, with just E geometry at the C-10/C-11 alkene. Sub-
sequent purifications afforded E 30 contaminated with traces of Z
isomer at C-2. The spectral data for 30 (1H NMR) were almost iden-
tical to that of a similar product described in the literature.8b
The synthetic sequence was completed by cleavage of the silyl
ether and cyclohexylidene ketal upon treatment of 30 with DOW-
EX affording ethyl deoxymonate B 11 (2.2%) in 17 linear steps (21
steps total) from commercially available 4-pentyn-2-ol (Scheme 6).
The previous synthesis obtained the related methyl deoxypseu-
11. Kozikowski, A. P.; Schmiesing, R. J.; Sorgi, K. L. J. Am. Chem. Soc. 1980, 102,
6577–6580.
12. The scale in the preparation of fragment 29 proved to be critical. No
methylation of ethyl (S)-3-hydroxybutyrate was observed at small scale or in
the absence of DMPU.
domonate B in 21 linear steps (29 steps total) from L
-lyxose.8b