Formal synthesis of ent-dysiherbaine from sulfinyl dihydropyrans by sigmatropic rearrangement and tethered aminohydroxylation

Article abstract of DOI:10.1016/j.tetlet.2007.09.103

A stereospecific [2,3]-sigmatropic rearrangement of a sulfinyl dihydropyran, followed by a tethered aminohydroxylation reaction, are the key steps of a formal synthesis of ent-dysiherbaine from an enantiopure sulfinyl dienol.

Full text of DOI:10.1016/j.tetlet.2007.09.103

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8141–8144
Formal synthesis of ent-dysiherbaine from sulfinyl dihydropyrans by
sigmatropic rearrangement and tethered aminohydroxylation
*
´
Roberto Fernandez de la Pradilla, Nadia Lwoff and Alma Viso
Instituto de Quı´mica Orga´nica, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain
Received 13 August 2007; accepted 17 September 2007
Available online 21 September 2007
Abstract—A stereospecific [2,3]-sigmatropic rearrangement of a sulfinyl dihydropyran, followed by a tethered aminohydroxylation
reaction, are the key steps of a formal synthesis of ent-dysiherbaine from an enantiopure sulfinyl dienol.
Ó 2007 Elsevier Ltd. All rights reserved.
Tetrahydropyrans are key fragments of many natural
and bioactive products, such as (À)-dysiherbaine 1
(Scheme 1). This neurotoxic aminoacid was first isolated
in 1997 from the marine sponge Dysidea herbacea and
presents very interesting biological activity as a potent
agonist of non-NMDA type glutamate receptors in the
central nervous system.1 The structure of 1 was deter-
mined by extensive spectroscopic studies to be an
unprecedented diamino dicarboxylic acid, which is char-
acterized by a structurally novel cis-fused hexahydro-
furo[3,2-b]pyran ring system containing a glutamate
substructure. The potent biological activity and struc-
tural novelty has led to many approaches towards the
synthesis of dysiherbaine.2 Recently, Chamberlin
described the use of the Donohoe tethered amino-
hydroxylation reaction,3a to install the amino diol and
create the four contiguous stereocenters in the tetra-
hydropyran ring and completed the synthesis of an
advanced synthetic intermediate.2j In this Letter, we
report a formal synthesis of ent-dysiherbaine that fea-
tures a stereospecific [2,3]-sigmatropic rearrangement
and a tethered aminohydroxylation as the key steps; this
chemistry evolves from our desire to develop applica-
tions of our novel methodology to prepare dihydropyr-
anyl allylic sulfoxides.4
Me
O
O
Me
NH
N
CO2H
NH2
H
H
H
N
HO
O
O
O
CO2H
O
O
H
1
(−)-Dysiherbaine,
2
O
O
Bn
O
S
H
SO -Tol
2p
HO
SO -Tol
2p
-Tol
p
2
A few years ago, we reported the selective base-pro-
moted cyclization of enantiopure sulfinyl dienols to
afford configurationally stable allylic sulfinyl dihydro-
pyrans like 3a (Scheme 1).4 Within the context of the
different studies of reactivity, this structure was
subjected to dihydroxylation and elimination to obtain
vinyl sulfone 4. Formation of the benzyl carbamate
and cyclization under basic conditions afforded oxazo-
lidinone 5 in excellent yield.4 This model substrate
presented the relative stereochemistry enantiomeric to
dysiherbaine aside from the sulfone-bearing center. A
reasonable option to convert a structure related to 5 into
the required functionality would imply the transforma-
tion of the sulfone moiety into a carbonyl group,5 and
a straightforward reduction to the desired a-hydroxyl.
O
5
Ph
O
Ph
O
Ph
3a
4
O
O
O
O
Me
NH
N
H
O
OH
HO
?
?
?
O
R
R
O
O
O
H
A
B
ent-2
Scheme 1. Structure of dysiherbaine and synthetic intermediate 2.
Previous approach and synthetic strategy.
Keywords: Allylic sulfoxides; Sigmatropic rearrangement; Tethered
aminohydroxylation.
*
Corresponding author. Tel.: +34 91 562 29 00; fax: +34 91 564 48
53; e-mail: iqofp19@iqog.csic.es
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.103

8142
R. Ferna´ndez de la Pradilla et al. / Tetrahedron Letters 48 (2007) 8141–8144
Typically, this transformation requires a metalation at
the sulfone-bearing center and the capture of the anion
with an oxygen-based electrophile. The precise structure
of these intermediates, with two good leaving groups
flanking the reactive metalated sulfone, suggested that
competing b-eliminations could be important in this
case. These considerations prevented us from pursuing
this route further.
in toluene, solved the problem of the sigmatropic rear-
rangement step, leading to the desired allylic alcohol in
good yields and as a single isomer.8
To test the viability of the initial part of the synthetic
scheme, we then focused on the known and easily avail-
able substrate 3b (Scheme 2), that underwent a smooth
sigmatropic rearrangement to produce the correspond-
ing trans allylic alcohol, which was converted into the
cis isomer 8 by a Mitsunobu reaction.9 The treatment
of allylic alcohol 8 with trichloroacetylisocyanate
followed by aqueous K2CO3 in MeOH afforded carba-
mate 9 in excellent yield. Aminohydroxylation of carba-
mate 9, under the conditions originally described by
Donohoe,3a gave the desired product in 21–24% yield,
along with 15–33% recovered starting material.10,11 All
efforts to improve the yield of this transformation, includ-
ing a change of ligand to (DHQ)2PHAL, changes of the
batches and the sources of the reagents, etc., proved to
be fruitless. Nonetheless, this model study was completed
by N-methylation to afford 10 in 66% yield.
At this stage, we evaluated an alternate approach start-
ing from an allylic sulfoxide related to 3a with the
appropriate functionalization at C-2 that could be trans-
formed into alcohol A by a [2,3]-sigmatropic rearrange-
ment in the presence of a thiophile and subsequently
into B by a tethered aminohydroxylation protocol
(Scheme 1). This structure, after the transformations
of the side chain at C-2 could be converted into ent-2,
enantiomer of the intermediate used in a total synthesis
of dysiherbaine.2c The key step of the synthetic plan was
the sigmatropic rearrangement of an allylic sulfoxide
similar to 3a to an allylic alcohol A.6
In the preliminary studies, we had found remarkable dif-
ferences in the rate and the yield of the sigmatropic rear-
rangements of diastereomeric allylic sulfoxides (Scheme
2).4 Thus, sulfoxide 6 with 2,3-trans relative configura-
tion afforded alcohol 7a in excellent yield, but in the case
of the 2,3-trans diastereoisomers 3a and 3b, longer reac-
tion times were required only to obtain poor yields of
the corresponding products ent-7a and ent-7b. Since
we planned to base our synthesis in a 2,3-trans allylic
sulfoxide similar to 3a and 3b these results posed a
major problem which had to be overcome to validate
our synthetic approach. After considerable experimenta-
tion with different substrates, thiophilic agents, solvents
and temperatures, we found that changing the reaction
conditions from trimethyl phosphite in MeOH (the most
common protocol for this type of reaction),7 to DABCO
At this stage, we decided to carry on with the formal
synthesis of ent-dysiherbaine, with the expectation that
the outcome of the aminohydroxylation could be
improved for the precise substrate required and our
efforts are gathered in Scheme 3. To install the appro-
priate side chain at C-2 that allowed for the formation
of the butyrolactone in the final structure, we started
the synthesis from 3-butyn-1-ol 11. After the protection
of hydroxyl group as a TBDPS ether, the alkynyl sulfox-
ide 12 was formed by the reaction with EtMgBr and (À)-
menthyl p-toluenesulfinate. Hydrostannylation of 12
and tin–iodine exchange led to vinyl iodide 13, which
was subjected to a Stille coupling with hydroxy vinyl
stannane 14 to give sulfinyl diene 15 in excellent yield.
Base-promoted cyclization with LDA afforded sulfinyl
dihydropyran 16 as a single isomer. The modified condi-
tions for the [2,3]-sigmatropic rearrangement worked
perfectly on allylic sulfoxide 16 to produce allylic alco-
hol 17, which was inverted by a Mitsunobu protocol
to give 3,6-cis alcohol 18.12
O
H
S
HO
HO
10 equiv P(OMe)3
-Tol
-Tol
p
p
MeOH, 60 °C
12 h, 100%
O
6
Ph
O
7a
Ph
R
Treatment of alcohol 18 with trichloroacetylisocyanate
followed by aqueous K2CO3 as described above gave a
carbamate in excellent yield (structure not shown); this
carbamate was submitted to the original conditions for
aminohydroxylation,3a to afford a disappointing 26%
yield of oxazolidinone 20 along with 50% recovered
starting material. In addition, 20 was often produced
along with variable amounts of a regioisomeric oxazo-
lidinone; related isomerizations have been described by
Chamberlin and Handa.2j,11 This isomerization, along
with the poor yield obtained for the aminohydroxyl-
ation represented a major drawback for the success of
the sequence.
O
S
H
10 equiv P(OMe)3
MeOH, 50 °C
O
R
O
3a R = Ph
3b R = Bu
4 days
3 days
ent-7a 50%
ent-7b
19%
Me
O
O
NH2
O
N
H
O
S
HO
i, ii
O
OH
-Bu
-Tol
p
iii
iv, v
O
-Bu
O
-Bu
n
n
O
-Bu
O
n
n
3b (5 steps)
8
9
10
Scheme 2. Previous results on sigmatropic rearrangements. Synthesis
of model oxazolidinone 10. Reagent and conditions: (i) DABCO,
toluene, 70 °C, 83%; (ii) (a) PPh3, p-nitrobenzoic acid, DIAD, THF, rt.
(b) K2CO3, MeOH, rt, 86%; (iii) (a) Cl3CCONCO, CH2Cl2, 0 °C. (b)
K2CO3 (aq), MeOH, 0 °C–rt, 92%; (iv) K2OsO2(OH)4, tBuOCl,
NaOH, DIPEA, PrOH, rt, 21–24%, 15–33% recovered starting
material; (v) MeI, BaO, Ba(OH)2, DMF, 0 °C, 66%.
At this time, Donohoe reported a modification on the
original conditions for the tethered aminohydroxylation
that entailed the use of N-sulfonyloxy derivatives.3g This
new protocol allowed for the reaction to proceed with-
out a chlorinating agent (t-BuOCl) or hydroxide base.
Encouraged by this alternative, we decided to examine

R. Ferna´ndez de la Pradilla et al. / Tetrahedron Letters 48 (2007) 8141–8144
8143
O
O
O
S
O
S
H
I
S
S
-Tol
p
HO
-Tol
p
-Tol
p
-Tol
p
i, ii
v
iii, iv
vi
vii
OH
O
O
SnBu3
12
11
13 OTBDPS
15
16
17
OTBDPS
OTBDPS
OTBDPS
OH
OH
OTBDPS
14
viii
H
O
O
O
O
O
Me
O
N
OSO2Mes
O
N
NH
O
NH
H
H
O
O
HO
O
O
OH
xiv
xii, xiii
xi
ix, x
O
O
O
O
O
H
H
ent-2
21
20
19
18
OTBDPS
OTBDPS
OTBDPS
Scheme 3. Formal synthesis of ent-dysiherbaine. Reagent and conditions: (i) TBDPSCl, imidazole, CH2Cl2, 0 °C–rt, 100%; (ii) (a) EtMgBr, Et2O. (b)
(À)-Menthyl p-toluenesulfinate, toluene, À20 °C, 89%; (iii) Bu3SnH, Pd(PPh3)4, toluene, À78 °C–rt, 83%; (iv) I2, CH2Cl2, rt, 88%; (v) 14, AsPh3,
BHT, Pd2(dba)3ÆCHCl3, THF, rt, 94%; (vi) LDA, THF, À78 °C–rt, 89%; (vii) DABCO, toluene, 70 °C, 93%; (viii) (a) PPh3, p-nitrobenzoic acid,
DIAD, THF, rt. (b) K2CO3, MeOH, rt, 81%; (ix) (a) CDI, MeCN, rt. (b) Imidazole, NH2OH, 0 °C, 86%; (x) MesSO2Cl, Et3N, toluene–DMF, 0 °C,
88%; (xi) K2OsO2(OH)4, DIPEA, PrOH-H2O, rt, 77%; (xii) DOWEX, MeOH, rt, 100%; (xiii) TEMPO, (diacetoxyiodo)benzene, CH2Cl2, rt, 84%;
(xiv) NaH, MeI, THF–DMF, À40 °C, 59%, 19% recovered starting material.
(c) Masaki, H.; Maeyama, J.; Kamada, K.; Esumi, T.;
Iwabuchi, Y.; Hatakeyama, S. J. Am. Chem. Soc. 2000,
122, 5216–5217; (d) Phillips, D.; Chamberlin, A. R. J. Org.
Chem. 2002, 67, 3194–3201; (e) Sasaki, M.; Akiyama, N.;
Tsubone, K.; Shoji, M.; Oikawa, M.; Sakai, R. Tetra-
hedron Lett. 2007, 48, 5697–5700; Partial and formal
syntheses: (f) Naito, T.; Nair, J. S.; Nishiki, A.; Yamash-
ita, K.; Kiguchi, T. Heterocycles 2000, 53, 2611–2615; (g)
Miyata, O.; Iba, R.; Hashimoto, J.; Naito, T. Org. Biomol.
Chem. 2003, 1, 772–774; (h) Kang, S. H.; Lee, Y. M.
Synlett 2003, 993–994; (i) Huang, J.-M.; Xu, K.-C.; Loh,
T.-P. Synthesis 2003, 755–764; (j) Cohen, J. L.; Chamber-
lin, A. R. Tetrahedron Lett. 2007, 48, 2533–2536; Related
studies: (k) Friestad, G. K.; Mathies, A. K. Tetrahedron
2007, 63, 9373–9381.
the modified procedure for the aminohydroxylation and
the required N-sulfonyloxy carbamate was readily
prepared by the sequential reaction of alcohol 18 with
carbonyldiimidazole and hydroxylamine, followed by
sulfonylation to afford 19 in good yield.13 The tethered
aminohydroxylation worked very well on this substrate
leading to oxazolidinone 20, containing the four contig-
uous cis stereocenters of the final structure in good yield.
Cleavage of the silyl ether with Dowex resin and selec-
tive oxidation of the primary alcohol with TEMPO
with concurrent cyclization led to butyrolactone 21.14
Finally, an N-methylation that required different condi-
tions to those used for the model substrate (Scheme 2)
completed the synthesis of tricyclic structure ent-2 that
had identical data to those described in the literature,
except for the sign of the optical rotation.2c
3. (a) Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan,
M. J. Am. Chem. Soc. 2002, 124, 12934–12935; (b)
Donohoe, T. J.; Johnson, P. D.; Helliwell, M.; Keenan,
M. Chem. Commun. 2001, 2078–2079; (c) Donohoe, T. J.;
Johnson, P. D.; Pye, R. J. Org. Biomol. Chem. 2003, 1,
2025–2028; (d) Donohoe, T. J.; Johnson, P. D.; Pye, R. J.;
Keenan, M. Org. Lett. 2004, 6, 2583–2585; (e) Kenworthy,
M. N.; McAllister, G. D.; Taylor, R. J. K. Tetrahedron
Lett. 2004, 45, 6661–6664; (f) Donohoe, T. J.; Johnson, P.
D.; Pye, R. J.; Keenan, M. Org. Lett. 2005, 7, 1275–1277;
(g) Donohoe, T. J.; Chughtai, M. J.; Klauber, D. J.;
Griffin, D.; Campbell, A. D. J. Am. Chem. Soc. 2006, 128,
2514–2515.
In conclusion, we have described the synthesis of dysi-
herbaine intermediate ent-2 based on an efficient [2,3]-
sigmatropic rearrangement of an allylic sulfoxide, and
a tethered aminohydroxylation step that allowed for
the creation of the four contiguous stereocenters. A
related approach to the malayamicin A core, with a
trans-fused hexahydrofuro[3,2-b]pyran ring system,
from 3,6-trans allylic alcohol 17 is currently under study.
´
4. Fernandez de la Pradilla, R.; Tortosa, M. Org. Lett. 2004,
6, 2157–2160.
Acknowledgements
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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 N.L.
`
6. For recent examples, see: (a) Brebion, F.; Najera, F.;
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12. Interestingly, the fully deprotected 3,6-cis-diol derived
from 18 could be obtained in a single step from allylic
sulfoxide 16 by the treatment with Na2S with good yield
and selectivity (90%, cis:trans, 91:9). Unfortunately,
selective protection to generate 18 was not efficient. These
results will be described in detail in due time.
13. We first studied the process for the tosyloxy derivative, but
the yields were moderate and the starting material was not
recovered, under these conditions. In contrast, the mesityl-
sulfonyloxy derivative was more stable and gave higher
yields in the aminohydroxylation step.
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scale and it has been previously reported that under these
conditions the yields vary unpredictably from 4% to 40%.
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Lett. 2005, 46, 5297–5300.
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