[2,3]-Sigmatropic rearrangements of 3-sulfinyl dihydropyrans: application to the syntheses of the cores of ent-dysiherbaine and deoxymalayamicin A

Article abstract of DOI:10.1021/jo8015709

(Chemical Equation Presented) The [2,3]-sigmatropic rearrangement of a variety of configurationally stable diastereomeric allylic sulfinyl dihydropyrans, produced by base-promoted cyclization of sulfinyl dienols, has been studied. In some cases, the effic

Full text of DOI:10.1021/jo8015709

[2,3]-Sigmatropic Rearrangements of 3-Sulfinyl Dihydropyrans:
Application to the Syntheses of the Cores of ent-Dysiherbaine and
Deoxymalayamicin A
´
´
Roberto Ferna´ndez de la Pradilla,* Nadia Lwoff, Miguel Angel del Aguila, Mariola Tortosa,
and Alma Viso
Instituto de Qu´ımica Orga´nica, CSIC, Juan de la CierVa, 3, 28006 Madrid, Spain
iqofp19@iqog.csic.es
ReceiVed July 23, 2008
The [2,3]-sigmatropic rearrangement of a variety of configurationally stable diastereomeric allylic sulfinyl
dihydropyrans, produced by base-promoted cyclization of sulfinyl dienols, has been studied. In some
cases, the efficient transformation of these substrates into dihydropyranols required an in-depth study of
reaction conditions, with the preferred protocol relying on the use of DABCO in warm toluene. This
methodology has been applied to the syntheses of the cores of ent-dysiherbaine and deoxymalayamicin
A by means of efficient tethered aminohydroxylations.
Introduction
for the creation of new functionalities.5 The conversion of
sulfoxides into allylic alcohols has been widely used with
synthetic purposes since it may benefit from the chiral auxiliary
properties of sulfoxides, and represents an easy procedure for
removal of the sulfur moiety which usually is not present in
final synthetic targets.6
During the past few years our group has developed the
stereocontrolled cyclization of hydroxy sulfinyl dienes with
different bases depending on the diene geometry to obtain
configurationally stable sulfinyl dihydropyrans 3-6 with 2,3-
trans and 2,3-cis relative configuration (Scheme 2).7 These
substrates present a peculiar arrangement of functionalities that
suggests that different reactivities should be considered, for
instance, under basic reaction conditions; these include oxygen
ꢀ-elimination and cleavage of the dihydropyran ring, epimer-
ization R to the sulfoxide, and for 2,3-trans substrates the
possible pyrolitic syn-elimination of the sulfoxide moiety.
The[2,3]-sigmatropic rearrangement of allylic sulfoxides to
allylic sulfenates originally developed by Mislow,1 Braverman,2
and Evans3 is a reversible process that can cause the racem-
ization of allylic sulfoxides I, via the intermediate sulfenate
esters II, that can transform into enantiomeric sulfoxides III
(Scheme 1).4 The presence of a suitable thiophile can cleave
the O-S bond in the sulfenate intermediate, rendering the
process irreversible by removing the sulfur atom and leading
to an allylic alcohol IV. Allylic alcohols are important sub-
structures in many bioactive products and also key building
blocks in organic synthesis since they can be involved in a
variety of stereocontrolled chemical transformations that allow
* To whom correspondence should be addressed. Fax: 34-91-564-4853.
(1) (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.
(2) Braverman, S.; Stabinsky, Y. J. Chem. Soc., Chem. Commun. 1967, 270–
271.
(3) Evans, D. A.; Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93,
4956–4957.
(4) (a) Braverman, S. In The Chemistry of Sulphones and Sulphoxides; Patai,
S., Rappoport, Z., Stirling, C. J. M., Eds.; John Wiley & Sons: New York, 1988;
p 717. (b) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147–155. (c)
Reggelin, M. Top. Curr. Chem. 2007, 275, 1–65.
(5) (a) Chen, Q.; Qing, F.-L. Tetrahedron 2007, 63, 11965–11972. (b)
Griesbeck, A. G.; El-Idreesy, T. T.; Lex, J. Tetrahedron 2006, 62, 10615–10622.
(c) Fournier, J. F.; Mathieu, S.; Charette, A. B. J. Am. Chem. Soc. 2005, 127,
13140–13141. (d) Adam, W.; Bottke, N. J. Am. Chem. Soc. 2000, 122, 9846–
9847. (e) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703–710.
(6) Recent examples: (a) Ferna´ndez de la Pradilla, R.; Lwoff, N. Tetrahedron
Lett. 2008, 49, 4167–4169. (b) Ferna´ndez de la Pradilla, R.; Lwoff, N.; Viso, A.
Tetrahedron Lett. 2007, 48, 8141–8144. (c) Brebion, F.; Na`jera, F.; Delouvrié,
B.; Lacoˆte, E.; Fensterbank, L.; Malacria, M. Synthesis 2007, 2273–2278. (d)
Pelc, M. J.; Zakarian, A. Tetrahedron Lett. 2006, 47, 7519–7523. (e) Koprowski,
M.; Krawczyk, E.; Skowron˜ska, A.; McPartlin, M.; Choi, N.; Radojevic, S.
Tetrahedron 2001, 57, 1105–1118. For an example retaining the sulfur atom
see: (f) Satoh, T.; Miyagawa, T. Tetrahedron Lett. 2006, 47, 1981–1983.
(7) (a) Ferna´ndez de la Pradilla, R.; Tortosa, M. Org. Lett. 2004, 6, 2157–
´
2160. (b) Ferna´ndez de la Pradilla, R.; Tortosa, M.; Lwoff, N.; del Aguila, M. A.;
Viso, A. J. Org. Chem. 2008, 73, 6716–6727.
10.1021/jo8015709 CCC: $40.75
Published on Web 10/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8929–8941 8929

Ferna´ndez de la Pradilla et al.
TABLE 1. Sigmatropic Rearrangement Using P(OMe)3 and
Et2NH as Thiophiles
SCHEME 1. Sigmatropic Rearrangement of Allylic
Sulfoxides
entry
substrate
thiophile
7:8 ratio
yield
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3c
3c
3c
3d
P(OMe)3
Et2NH
P(OMe)3
Et2NH
P(OMe)3
P(OMe)3
Et2NH
100:0
89:11
100:0
85:15
100:0
100:0
73:27
100:0
19%
85%
50%a
60%
27%
22%b
91%c
72%
SCHEME 2. Base-Mediated Cyclization of Hydroxy Sulfinyl
Dienes
P(OMe)3
a 50% of starting material recovered. b Temperature 60 °C, 39% of a
mixture of intermediates formed by MeOH capture was isolated (see
Supporting Information). c 8% of vinyl sulfoxide is isolated.
To the moment, these conformational factors that may cause
such a great difference in reactivity have been scarcely
documented for this process probably due to the intrinsic
configurational instability at sulfur of most allylic sulfoxides.
Since our methodology provided all four diastereomers of
substituted 3-sulfinyl dihydropyrans in some cases and they were
configurationally stable to a certain extent, we had a unique
opportunity to examine the behavior of all possible diastereo-
mers in the [2,3]-sigmatropic rearrangement. Therefore, we
decided to carry out a thorough study of the process with
different substrates and conditions with the intent of finding
optimized conditions to obtain synthetically useful dihydropy-
ranols in a relatively short reaction sequence.
SCHEME 3. Sigmatropic Rearrangement of Allylic
Sulfoxides
Trying to improve the process for less reactive substrates like
3b, we tried other thiophilic agents such as Et2NH, improving
yields, but obtaining mixtures of 3,6-trans and 3,6-cis diaster-
eomers, 7 and 8 (Table 1). For aliphatic substrate 3a the reaction
with P(OMe)3 afforded only the expected trans alcohol 7a but
in low yield (Table 1, entry 1). The use of Et2NH improved the
yield but a mixture of isomers was obtained (Table 1, entry 2).
The behavior was similar for substrate 3b with an aromatic
substituent (Table 1, entries 3 and 4) and also for 2,6-
disubstituted sulfinyl dihydropyran 3c (Table 1, entries 5 and
7). When the rearrangement of 3c with P(OMe)3 was carried
out at higher temperature, a mixture of products resulting from
capture of the intermediates with MeOH was obtained along
with the product (Table 1, entry 6). In contrast, diasteromeric
substrate 3d afforded 7d as a single isomer and in good yield
by reaction with P(OMe)3 (Table 1, entry 8). The different
selectivities found for Et2NH relative to P(OMe)3 suggested that
different reaction pathways were operative for these thiophiles.
Moreover, the intrinsic configurational stability of the majority
of these allylic sulfoxides suggests that the [2,3]-sigmatropic
rearrangement is not a favored pathway for these substrates. In
this paper we report in full our studies on the reactivity of these
allylic sulfoxides in the [2,3]-sigmatropic rearrangement under
different conditions. In addition, the application of this meth-
odology to the syntheses of the cores of ent-dysiherbaine and
deoxymalayamicin A by means of efficient tethered aminohy-
droxylations is also described.
Results and Discussion
Sigmatropic Rearrangement of 2,3-trans Sulfinyl Dihy-
dropyrans. Within the context of exploring the reactivity of
our sulfinyl dihydropyrans, we first studied the sigmatropic
rearrangement of diastereomeric 2,3-trans substrates 3b and 6b
under standard conditions [P(OMe)3/MeOH] to obtain the
corresponding 3,6-trans allylic alcohols. For substrate 6b the
reaction worked well in 12 h, while diastereomer 3b afforded
poor yields and long reaction times were required (Scheme 3).
Sulfinyl dihydropyrans 3b and 6b are enantiomeric except for
the configuration at sulfur, and yet they adopt different preferred
conformations; this suggests that conformational factors could
also be determinant for the viability of the sigmatropic process.
These results may be rationalized qualitatively on the basis
of the relative ease of attaining the reactive conformations that
place the sulfoxide in a pseudoaxial position with the oxygen
atom oriented toward the double bond for different diastereo-
meric allylic sulfoxides. The conformational analysis of the
substrates based on chemical shifts and coupling constants show
that the preferred conformations for 6b and 3d place the
sulfoxide in a pseudoequatorial position (Figure 1, conformers
V and VII), while isomers 3a-c locate the sulfoxide in a
8930 J. Org. Chem. Vol. 73, No. 22, 2008

[2,3]-Sigmatropic Rearrangements of 3-Sulfinyl Dihydropyrans
p-tolyl group pointing toward the dihydropyran ring in an
unfavorable scenario.10
We then studied another known thiophile, Na2S·9H2O in
MeOH, and found interesting results which were complementary
to those previously obtained (Table 2).11 For all substrates the
major product was 3,6-cis allylic alcohol 8 in similar ratios for
all types of substitution with the minor product ent-7 presenting
enantiomeric configuration at C-6. For substrates 3e and 3f
(prepared to study synthetic applications of this process, see
below), the silyl protecting group was cleaved in the presence
of Na2S·9H2O (entries 4, 5) both in the presence or absence of
an excess of base in the reaction media. Since the [2,3]-
sigmatropic rearrangement of allylic sulfoxides occurs as a
concerted process and the facial selectivity is determined by
the configuration of the sulfur-bearing center, from 2,3-trans
substrates 3 it would be expected to obtain 3,6-trans alcohols.
Therefore the results obtained with Na2S·9H2O implied that
an alternative reaction pathway was operative. The enantiomeric
purity of some of the alcohols obtained was evaluated by
derivatization with methoxyphenylacetic acid (see below).12
We hypothesized that formation of the major cis products
and products of the enantiomeric configuration at C-6, could
imply an epimerization at position 3 and/or a ring opening-
closing sequence (Scheme 4), which would give rise to the
formation of cis isomers 4 which are known to transform into
alcohols 8 easily.7b Therefore, to address this possibility, we
examined the behavior of dienyl sulfoxides 1, precursors of
dihydropyrans 3, under these reaction conditions. Interestingly
it was possible to carry out the cyclization and sigmatropic
rearrangement in one step for all substrates studied, obtaining
slightly different selectivities from the process with sulfinyl
dihydropyrans 3. Changing from MeOH to an aprotic solvent
like DMF (Table 2, entry 7), improved the selectivity but with
diminished yield due to formation of a considerable amount of
the corresponding vinyl sulfoxide.13 The use of lower excess
of reagent did not have much effect on the selectivity (Table 2,
entry 8). For Z,E diene 2b (not shown) in DMF, a complex
reaction mixture was recovered along with starting material.
The slightly different selectivities found for ent-7a-b and
8a-b when carrying out the reaction from 3a-b or from 1a-b
is likely to reflect the possibility of at least two potential reaction
pathways for the process supporting the hypothesis of coexist-
ence of epimerization at C-3 and ring opening-closing sequences.
The minor trans product ent-7a obtained from the reaction of
diene 1a (Table 2, entry 6) was not enantiomerically pure (50%
ee, see below). The fact that products of the enantiomeric series
were obtained suggested the possibility of formation of both
diastereomers of cis and trans dihydropyrans under the reaction
conditions, each of them evolving preferentially through the
most reactive isomers (Scheme 4). A tentative rationalization
of these results may even involve a partial isomerization of the
diene 1 to the Z,E isomer 2 and subsequent cyclization to obtain
dihydropyrans with enantiomeric configuration at C-2, 5 or 6
FIGURE 1. Proposed reactive conformations for 6b and 3a-d.
pseudoaxial arrangement (Figure 1, conformers IX and XI).7b,8
In addition, the chemical shift patterns for H-2 and H-4 in the
case of isomers 3a-c suggest that the preferred conformer may
place the oxygen atom away from the allylic moiety.
In the case of 6b and 3d, a simple conformational change
from one chair conformer to the alternative chair (6b) or to a
boat conformer (3d) would lead to the required pseudoaxial
arrangements (Figure 1, conformers VI and VIII),9 with the
p-tolyl group away from the dihydropyran ring in both cases.
It should be noted that the alternative chair conformer for 3d
(not shown) would present severe 1,3-diaxial interactions. For
substrates3a-c,aconformationalchangearoundthecarbon-sulfur
bond would be required to reach the reactive conformation. The
resulting reactive conformers for 3a,b (Figure 1, conformer X)
and for 3c (Figure 1, conformer XII) would place the bulky
(10) The conformation around the sulfur atom could also be influenced by
coordination of the sulfinyl and ring oxygens with the solvent thus increasing
the steric bulk around those atoms. See: (a) McNelis, B. J.; Sternbach, D. D.;
MacPhail, A. T. Tetrahedron 1994, 50, 6767–6782. (b) Roush, W. R.; Champoux,
J. A.; Peterson, B. C. Tetrahedron Lett. 1996, 37, 8989–8992.
(11) Evans, D. A.; Bryan, C. A.; Sims, C. L. J. Am. Chem. Soc. 1972, 94,
2891–2892.
(8) Tortosa, M. PhD thesis, Universidad Auto´noma de Madrid, 2005.
(9) (a) Goodwin, T. E.; Ratcliff, D. G.; Crowder, C. M.; Seitzinger, N. K. J.
Org. Chem. 1982, 47, 815–820. (b) Overman, L. E.; Petty, C. B.; Ban, T.; Huang,
G. T. J. Am. Chem. Soc. 1983, 105, 6335–6337. (c) Arribas, C.; Carren˜o, M. C.;
Garc´ıa Ruano, J. L.; Rodr´ıguez, J. F.; Santos, M.; Sanz-Tejedor, M. A. Org.
Lett. 2000, 2, 3165–3168.
(12) Supporting Information. See: (a) Latypov, S. K.; Seco, J. M.; Quin˜oa´,
E.; Riguera, R. J. Org. Chem. 1996, 61, 8569–8577. For a review on the
determination of absolute configuration by NMR, see: (b) Seco, J. M.; Quin˜oa´,
E.; Riguera, R. Chem. ReV. 2004, 104, 17–118.
(13) Stereochemistry of vinyl sulfoxide could not be determined.
J. Org. Chem. Vol. 73, No. 22, 2008 8931

Ferna´ndez de la Pradilla et al.
TABLE 2. Cyclization and Sigmatropic Rearrangement with Na2S·9H2O
entry
substrate
ent-7:8 ratio
yield
1
2
3
4
5
6
7
8
9
3a
3b
3c
3e
3f
1a
1a
1b
1c
19:81
11:89
0:100
6:94
0:100
30:70
5:95
68%
89%
100%
89%a
100%a
79%
53%b
96%c
75%
34:66
6:94
a Deprotected alcohols 8g and ent-7g were obtained. b Reaction carried out in DMF; 1H NMR of the crude product was a 70:4:26 mixture of 8a,
ent-7a and the corresponding vinyl sulfoxide (8% isolated yield) (not shown, see Supporting Information). c Reaction carried out with 6.7 equiv of
Na2S·9H2O.
SCHEME 4. Possible Reaction Pathway for the Formation
of Alcohols 8 and ent-7
elimination product in MeOH to affording the [2,3]-sigmatropic
rearrangement product in benzene.9b,15
In addition to the thiophiles already mentioned, many different
thiophilic bases, such as piperidine, K2CO3, Mg(OMe)2, or
DABCO, have been used in the past to carry out the conversion
of allylic sulfoxides to allylic alcohols with variable results.16
In the context of previous studies on the cyclization of hydroxy
sulfinyl dienes with phosphazenes in different solvents, we had
obtained small amounts of rearrangement product (allylic
alcohol) so we decided to explore the use of hindered bases as
thiophilic agents for the process.7b A change of solvent from
MeOH to toluene, which allowed for an increase in the reaction
temperature from 50 to 70 °C and at the same time might
influence the viability and rate of the process, perhaps favoring
the desired [2,3]-sigmatropic rearrangement, led us from 2,3-
trans sulfoxides 3 to trans allylic alcohols 7 with complete
stereoselectivity and good yields. We studied several hindered
bases under the new conditions and the results are gathered in
Table 3. The use of BEMP apparently caused some epimeriza-
tion of the starting material, affording trans alcohols and a small
amount of cis isomer (Table 3, entry 1). Amine and amidine
type bases such as DABCO (Table 3, entries 2-5), DBU (Table
3, entries 6, 7 and 8), DBN (Table 3, entry 9) or quinuclidine
(Table 3, entry 10), afforded the expected product with complete
selectivity for substrates bearing aromatic and aliphatic sub-
stituents as well as for the C-4 substituted derivative 3h.17,18 In
contrast, the yield for the reaction with P(OMe)3 was only
or simply that the cyclizations of dienols 1 have diminished
selectivities under these conditions. Furthermore, it appears that
Na2S is sufficiently basic to promote epimerization at C-3 and/
or ring-cleavage for sulfinyl dihydropyrans 3 leading to dienols
1 or 2.
At this stage, we had not found a satisfactory solution for
the sigmatropic rearrangement of 2,3-trans substrates 3, the most
readily available diastereomers from our methodology. There-
fore, we explored other possibilities that could solve this problem
and lead to an improvement of the process for these substrates.
It has been reported that solvent effects have a profound
influence on the rate of [2,3]-sigmatropic rearrangements.1b,14
Usually, polar solvents stabilize sulfoxides by solvation decreas-
ing the sulfoxide-sulfenate conversion rate. There are examples
in the literature where a change of solvent modulates the
reactivity of allylic sulfoxides, from obtaining the pyrolitic syn-
(15) Posner, G. H.; Haces, A.; Harrison, W.; Kinter, C. M. J. Org. Chem.
1987, 52, 4836–4841.
(16) (a) Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672–
3674. (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Restelli, A.
Gazz. Chim. Ital. 1985, 115, 637–641.
(14) Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc. 1995, 117,
9077–9078.
8932 J. Org. Chem. Vol. 73, No. 22, 2008

[2,3]-Sigmatropic Rearrangements of 3-Sulfinyl Dihydropyrans
TABLE 3. Sigmatropic Rearrangement with Hindered Bases
entry
substrate
base
BEMP
DABCO
DABCO
DABCO
DABCO
DBU
DBU
DBU
DBN
Quinuclidine
P(OMe)3
Et2NH
7:8 ratio
yield
1
2
3
4
5
6
7
8
3a
3a
3b
3e
3h
3a
3b
3e
3b
3b
3a
3a
97:3
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
84%
77%
90%
93%
41%
53%
92%
70%
67%
69%
42%
83%
9
10
11
12
TABLE 4. Sigmatropic Rearrangement of cis Isomer 5a
SCHEME 5. Sigmatropic Rearrangement of cis Isomers 4
entry
thiophile agent
ent-7a:ent-8a ratio
yield
a
1
2
3
4
5
P(OMe)3
Et2NH
Na2S·9H2O
DABCO
Et2NH
-
-
72:28
100:0
0:100
0:100
100%a
70%a
48%b
53%c
improved slightly with the new conditions (Table 3, entry 11).
It appears that the effect of the solvent is the main cause for
the improvement in the stereoselectivity, as the reaction of 3a
with Et2NH in toluene yields only trans product (Table 3, entry
12; compare to Table 1, entry 2). We hypothesized that toluene
would minimize solvation of the oxygen atoms and therefore
would lead to less restricted conformations around the
sulfur-carbon bond, allowing for the oxygen to be placed in
the appropriate position to interact with the allylic center.
Sigmatropic Rearrangement of 2,3-cis Sulfinyl Dihydro-
pyrans. The reaction of 2,3-cis isomers 4 with P(OMe)3 in
MeOH proceeded smoothly for substrates with aliphatic and
aromatic substituents (Scheme 5), leading to the expected 3,6-
cis alcohols 8 as single isomers in moderate to good yields.
The conformational analysis for 4a-b suggested a pseudoaxial
arrangement of the sulfoxide, with the oxygen oriented toward
the double bond and the p-tolyl group facing away from the
ring (Figure 2). Since it seems that no change of conformation
is required to adopt the required conformation, the process is
likely to have a lower activation energy which would explain
the fact that these substrates rearrange almost spontaneously at
room temperature in CH2Cl2 solution.
a Reaction carried out in MeOH. b Reaction carried out in toluene.
c Reaction carried out in toluene; 13% of vinyl sulfoxide isolated.
FIGURE 2. Proposed conformations for 4a-b.
isomers with the trans isomer ent-7a as the major product (note
that the main product should be cis as the process is expected
to occur with retention of configuration). This suggests a
possible epimerization at position 3 of the sulfoxide to give a
reactive trans substrate similar to 6b that would rearrange easily
to form the trans allylic alcohol. The low value of the optical
rotation of diastereomerically pure ent-7a derived from 2,3-cis
substrate 5a (Table 4, entry 3, see Supporting Information)
suggests that, to some extent, the reaction pathway in this case
involvesaring-cleavagefollowedbycyclizationandrearrangement.
In contrast, under the new conditions, 2,3-cis sulfoxide 5a
gave the expected cis isomer ent-8a as a single product, but
only in moderate yields (Table 4, entries 4 and 5). The reactive
conformation for 5a (Figure 3) would place the p-tolyl group
pointing toward the dihydropyran ring thus leading to strong
steric interactions with the cis side chain at C-2.
In contrast, diastereomeric 2,3-cis substrate 5a was not
reactive with P(OMe)3 (Table 4, entry 1). When the conditions
were changed to Et2NH at 65 °C, we obtained a mixture of
(17) Bicyclic amidines DBU and DBN have been termed as “nonnucleophilic
strong bases” but numerous examples have been reported which demonstrate
that they can also act as nucleophiles. For examples, see: Baidya, M.; Mayr, H.
Chem. Commun 2008, 1792–1794, and references therein.
(18) The reaction mixture had to be carefully degassed before closing the
system and heating at 70 °C for the yields to be reproducible.
Stereochemical Assignments. Since the spectroscopic data
for ent-7b was ambiguous (J2ax-3 ) 5.4 Hz, J2eq-3 ) 4.4 Hz) we
prepared acetate ent-9b by acetylation and the inversion product
J. Org. Chem. Vol. 73, No. 22, 2008 8933

Ferna´ndez de la Pradilla et al.
SCHEME 7. Derivatization of 7a and 8a
FIGURE 3. Proposed reactive conformer for 5a.
SCHEME 6. Acetylation and Mitsunobu Reactions
SCHEME 8. Derivatization of ent-7a and ent-8
The absolute stereochemistry of allylic alcohols 7a (from 3a
and DABCO) and 8a (from 3a and Na2S and independently,
from 4a and P(OMe)3) was determined by the preparation of
the (S) and (R)-methoxyphenyl acetates 11, 12, 13 and 14
(Scheme 7).12 In addition, we have examined several derivati-
zations of products obtained with other thiophiles to gain insight
on their absolute configurations, and therefore on the possible
reaction pathways (Scheme 8).
The reaction with (+)-MPA of practically diastereomerically
pure ent-7a, derived from the cyclization and rearrangement of
1a with Na2S·9H2O, afforded only two diastereomers in 25:75
ratio, indicating that ent-7a had 50% ee (Scheme 8), and also
that alcohol ent-7a obtained in this manner had enantiomeric
configuration at C-6, thus supporting the hypothesis of ring
opening-closing sequence. Shielding effects observed on H-4
showed that the assignment for the alcohols was in agreement
with the results observed. On the other hand, a 63:37 diaster-
eomeric mixture of ent-7a and ent-8a, obtained from the reaction
of 5a with Et2NH, was derivatized with (+)-MPA to afford a
69:31 mixture of diastereomers ent-12a and ent-14a along with
recovered starting material and traces of 13a. This showed that
the alcohols were epimers at C-3, and that more than one
mechanism could be operating in the reaction, since a small
amount of 13a of the enantiomeric series was observed in the
mixture.
ent-10b by a Mitsunobu protocol.19 The coupling constants
between H3-H2eq and H3-H2ax indicated a pseudoaxial ar-
rangement for H3 for ent-9b and pseudoequatorial in ent-10b.
This represented a 3,6-trans relative stereochemistry for acetate
ent-9b and therefore for the precursor alcohol ent-7b. Based
on coupling constants values for H2 and H3 we could determine
the preferred conformation for alcohols 7a-e, where the
hydroxyl group is in a pseudoequatorial position (J2eq-3 ) 4.7
Hz, J2ax-3 ) 6.7 Hz) except for 7c where the methyl substituent
in C-2 is pseudoequatorial, with the phenyl and hydroxyl groups
pseudoaxial. For 8a-e the hydroxyl groups were pseudoaxial,
except for alcohol 8c which adopted a conformation where both
methyl and hydroxyl substituents had a pseudoequatorial
arrangement. To confirm the stereochemistry assigned to 7a and
8b they were converted into acetates 10a and 10b by Mitsunobu
inversion and acetylation respectively (Scheme 6), that had
coupling constants values similar to those obtained for ent-10b.
The same procedures were followed for alcohols 7c and 8c both
affording acetate 10c, and diastereomeric acetate 9c by acety-
lation of 7c.
Finally, 2,6-disubstituted alcohols 7c, 7d and 8c were also
derivatized with (+)-MPA to confirm their enantiomeric purity
to produce esters 11c, 11d and 13c respectively as single isomers
(Scheme 9). Due to lack of sufficient amounts of these samples
8934 J. Org. Chem. Vol. 73, No. 22, 2008

[2,3]-Sigmatropic Rearrangements of 3-Sulfinyl Dihydropyrans
FIGURE 5. Initial retrosynthetic scheme.
SCHEME 10. Model Studies for the Initial Approach to
ent-16
FIGURE 4. Structure of (-)-dysiherbaine and malayamicin A.
SCHEME 9. Derivatization of 7c, 7d, and 8c
activity and structural novelty has led to many approaches
toward the synthesis of dysiherbaine.21 On the other hand,
malayamicin A 17, a bicyclic C-nucleoside that exhibits
fungicide activity, was isolated from the soil organism Strep-
tomyces malaysiensis, and its structure was proposed by detailed
NMR studies and by degradation. The structure and stereo-
chemistry of 17 was confirmed by a stereocontrolled total
synthesis from D-ribonolactone,22 and that methodology has
been used to prepare semisynthetic analogues, N-malayamicin
A and related purine and pyrimidine nucleosides.23 In view of
this background, we considered exploring an approach to the
synthesis of ent-16, the enantiomer of a known intermediate in
the total synthesis of (-)-dysiherbaine,21e and to tricyclic
intermediate 18, the core of deoxymalayamicin A (Figure 4).
We report herein a full account of our studies toward the
synthesis of ent-dysiherbaine,6b based on the [2,3]-sigmatropic
rearrangement of sulfinyl dihydropyrans and a Donohoe tethered
aminohydroxylation.24 This last strategy has also been used by
other groups to install the amino diol and create the four
contiguousstereocentersinthetetrahydropyranringof(-)-dysiherbaine.21e,k
Our initial retrosynthetic analysis implied the formation of a
carbamate derivative A that could be obtained from an allylic
sulfone B with the appropriate functionalization at C-2. (Figure
5). At this stage, we chose to carry out a model study to test
the viability of the early steps of the sequence (Scheme 10).
Readily available allylic sulfinyl dihydropyran 3b (Scheme
10)7 was subjected to dihydroxylation affording sulfonyl diol
19 and elimination to obtain vinyl sulfone 20. Formation of
benzyl carbamate 21 and cyclization under basic conditions
afforded oxazolidinone 22 in excellent yield.8 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 22 into the required
functionality would imply the transformation of the sulfone
moiety into a carbonyl group,25 and a straightforward reduction
to the desired R-hydroxyl functionality. Typically this trans-
formation requires a metalation at the sulfone-bearing center
and capture of the anion with an oxygen-based electrophile. The
structure of these intermediates, with two good leaving groups
we could not carry out the reaction with (()-MPA, so strictly,
the absolute configuration for these alcohols could not be
confirmed. However, a spectroscopic analysis related to the
previous one was done for all 2-methoxy-2-phenylacetic deriva-
tives, observing that the methyl group at C-2 in 11c and 11d
was shielded while H-4 was shielded in 13c relative to the
precursor alcohols. These results were similar to those observed
for alcohols 7a and 8a and their corresponding methoxyphenyl
acetates. Therefore assuming a similar behavior for alcohols
7c-d and 8c we tentatively assigned the absolute configurations
shown in Scheme 9.
Synthetic Applications. Having developed efficient condi-
tions to perform the [2,3]-sigmatropic rearrangement of 2,3-
trans substrates 3 in good yields and selectivities, we addressed
the synthetic applications of the process. We focused our
attention in natural products such as (-)-dysiherbaine 15 and
malayamicin A 17 (Figure 4) with a bicyclic tetrahydropyran-
tetrahydrofuran core. (-)-Dysiherbaine is a neurotoxic ami-
noacid first isolated in 1997 from the marine sponge Dysidea
herbacea that presents very interesting biological activity as a
potent agonist of non-NMDA type glutamate receptors in the
central nervous system.20 The structure of 15 was determined
by extensive spectroscopic studies to be an unprecedented
diamino dicarboxylic acid, which is characterized by a structur-
ally novel cis-fused hexahydrofuro[3,2-b]pyran ring system
containing a glutamate substructure. The potent biological
J. Org. Chem. Vol. 73, No. 22, 2008 8935

Ferna´ndez de la Pradilla et al.
SCHEME 11. Synthetic Strategy for the Syntheses of ent-16
and 18
flanking the reactive metalated sulfone, suggested that competing
ꢀ-eliminations could be important in this case. These consid-
erations, along with the considerable length of the synthetic plan,
prevented us from pursuing this route further.
Taking advantage of the possibility of obtaining 3,6-cis and
trans dihydropyranols from a common sulfinyl dihydropyran,
we evaluated an alternative approach starting from an allylic
sulfoxide related to 3b with the appropriate functionalization
at C-2 that could be transformed into alcohols C and E by a
[2,3]-sigmatropic rearrangement in the presence of a thiophile,6
and subsequently into D and F respectively by a tethered
aminohydroxylation protocol (Scheme 11). Structure D after
transformations of the side chain at C-2 could be converted into
ent-16, enantiomer of the intermediate used in a total synthesis
of (-)-dysiherbaine.21c From intermediate F a similar strategy
could be applied to prepare 18 which presents the bicyclic core
and functionality of deoxymalayamicin A.
SCHEME 12. Model Study for the Synthesis of ent-16
To test the viability of the initial part of the synthetic scheme
for ent-16, we focused on the known and easily available
compound 3a (Scheme 12) that underwent a smooth sigmatropic
rearrangement under the new conditions, to produce the corre-
sponding trans allylic alcohol stereoselectively that was con-
verted into cis isomer 8a by a Mitsunobu reaction.19 As already
discussed, the less readily available sulfoxide 4a could be
directly transformed into 8a in one step and in good yield.
Treatment of allylic alcohol 8a with trichloroacetylisocyanate
followed by aqueous K2CO3 in MeOH afforded carbamate 23a
in excellent yield. Aminohydroxylation of carbamate 23a, under
the conditions originally described by Donohoe,24a gave the
(19) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127–164.
(20) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem. Soc.
1997, 119, 4112–4116.
(21) Total syntheses: (a) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2000, 2,
635–638. (b) Sasaki, M.; Koike, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett.
2000, 41, 3923–3926. (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)
Takahashi, K.; Matsumura, T.; Ishihara, J.; Hatakeyama, S. Chem. Commun.
2007, 4158–4160. (f) Sasaki, M.; Tsubone, K.; Aoki, K.; Akiyama, N.; Shoji,
M.; Oikawa, M.; Sakai, R.; Shimamoto, K. J. Org. Chem. 2008, 73, 264–273.
Partial and formal syntheses: (g) Naito, T.; Nair, J. S.; Nishiki, A.; Yamashita,
K.; Kiguchi, T. Heterocycles 2000, 53, 2611–2615. (h) Miyata, O.; Iba, R.;
Hashimoto, J.; Naito, T. Org. Biomol. Chem. 2003, 1, 772–774. (i) Kang, S. H.;
Lee, Y. M. Synlett 2003, 993–994. (j) Huang, J.-M.; Xu, K.-C.; Loh, T.-P.
Synthesis 2003, 755–764. (k) Cohen, J. L.; Chamberlin, A. R. Tetrahedron Lett.
2007, 48, 2533–2536. (l) See also ref 6a. Related studies: (m) Lygo, B.; Slack,
D.; Wilson, C. Tetrahedron Lett. 2005, 46, 6629–6632. (n) Cohen, J. L.; Limon,
A.; Miledi, R.; Chamberlin, A. R. Bioorg. Med. Chem. Lett. 2006, 16, 2189–
2194. (o) Sasaki, M.; Tsubone, K.; Shoji, M.; Oikawa, M.; Shimamoto, K.; Sakai,
R. Bioorg. Med. Chem. Lett. 2006, 16, 5784–5787. (p) Friestad, G. K.; Mathies,
A. K. Tetrahedron 2007, 63, 9373–9381.
desired product 24a in 21-24% yield, along with 15-33%
recovered starting material.26,27 All efforts to improve the yield
of this transformation, including a change of ligand to
(DHQ)2PHAL, changes of the batches and sources of reagents,
etc., proved to be fruitless. Nonetheless, this model study was
completed by N-methylation to afford 25a in 66% yield.
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 13.
We started the synthesis from commercially available 4-(tert-
butyldimethylsilyloxy)-1-butyne 27f in order to prepare sulfinyl
dihydropyran 3f. The synthesis of the corresponding alkynyl
sulfoxide took place in very low yield, and the sigmatropic
rearrangement of 3f with Na2S·9H2O (Table 2, entry 5) planned
to obtain 8f, led to the 3,6-cis deprotected derivative 8g as we
have already discussed. Unfortunately selective protection of
the primary alcohol to generate 8f was not efficient and therefore
we considered using the TBDPS derivative instead, expecting
it to be stable in the sigmatropic rearrangement step.28 Therefore
(22) Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G. Org. Lett. 2003,
5, 4277–4280.
(23) (a) Hanessian, S.; Huang, G.; Chenel, C.; Machaalani, R.; Loiseleur,
O. J. Org. Chem. 2005, 70, 6721–6734. (b) Hanessian, S.; Marcotte, S.;
Machaalani, R.; Huang, G.; Pierron, J.; Loiseleur, O. Tetrahedron 2006, 62,
5201–5214.
(24) (a) Donohoe, T. J.; Johnson, P. D.; Helliwell, M.; Keenan, M. Chem.
Commun. 2001, 2078–2079. (b) Donohoe, T. J.; Johnson, P. D.; Cowley, A.;
Keenan, M. J. Am. Chem. Soc. 2002, 124, 12934–12935. (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. (h)
Donohoe, T. J.; Bataille, C. J. R.; Gattrell, W.; Kloesges, J.; Rossignol, E. Org.
Lett. 2007, 9, 1725–1728.
(25) (a) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43,
188–196. (b) Baudin, J.-B.; Julia, M.; Rolando, C. Tetrahedron Lett. 1985, 26,
2333–2334. (c) Hwu, J. R. J. Org. Chem. 1983, 48, 4432–4433. (d) Chemla, F.;
Julia, M.; Uguen, D. Bull. Soc. Chim. Fr. 1993, 130, 547–553. (e) Hoppe, D.;
Tebben, P.; Reggelin, M.; Bolte, M. Synthesis 1997, 183–189. (f) Fujishima,
H.; Takeshita, H.; Toyota, M.; Ihara, M. J. Org. Chem. 2001, 66, 2394–2399.
(26) Lwoff, N. MS thesis, Universidad Complutense de Madrid, September
2005.
(27) The tethered aminohydroxylation was carried out in small scale and it
has been previously reported that under these conditions the yields vary
unpredictably from 4 to 40%. See: Curtis, K. L.; Fawcett, J.; Handa, S.
Tetrahedron Lett. 2005, 46, 5297–5300.
(28) Since the exploratory study with a TBDMS silyl ether was carried out
at small scale, and the sequence was not completed, the intermediates could not
be fully characterized.
(29) Merten, J.; Hennig, A.; Schwab, P.; Fro¨hlich, R.; Tokalov, S. V.; Gutzeit,
H. O.; Metz, P. Eur. J. Org. Chem. 2006, 1144–1161.
8936 J. Org. Chem. Vol. 73, No. 22, 2008

[2,3]-Sigmatropic Rearrangements of 3-Sulfinyl Dihydropyrans
SCHEME 13. Synthesis of Alcohol 8e
SCHEME 14. Alternative Procedures To Obtain Alcohol 8e
of oxazolidinone 24e, along with 50% recovered starting
material. In addition, 24e was often produced along with variable
amounts of a regioisomeric oxazolidinone 34e that could be
originated due to the presence of base in the reaction media;
related isomerizations have been described by Chamberlin and
Handa.21k,27 This isomerization, along with the poor yield
obtained for the aminohydroxylation, represented a major
drawback for the success of the sequence.
At this time Donohoe reported a modification on the original
conditions for the tethered aminohydroxylation that entailed the
use of N-sulfonyloxy derivatives.24g This new protocol allowed
for the reaction to proceed without chlorinating agent (t-BuOCl)
or hydroxide base. Encouraged by this alternative we decided
to examine the modified procedure for the aminohydroxylation
and the required N-sulfonyloxy carbamate was readily prepared
by sequential reaction of alcohol 8e with carbonyldiimidazole
and hydroxylamine to obtain 32e, followed by sulfonylation to
afford 33e in good yield. We first studied the aminohydroxy-
lation for the tosyloxy derivative, but the yields were low (25%)
and the starting material was not recovered. In contrast, the
mesitylsulfonyloxy derivative 33e resulted more stable and gave
higher yields in the key step. The tethered aminohydroxylation
worked very well on this substrate leading to the expected
oxazolidinone 24e that contains the four contiguous cis stereo-
centers of the target. The regiochemistry of the product was
confirmed by NOE measurements on acetate 37e. Cleavage of
the silyl ether of 24e with Dowex (no reaction was observed
with TBAF) afforded diol 35e and selective oxidation of the
primary alcohol to the acid with TEMPO with concurrent
cyclization led to butyrolactone 36e.29 Finally an N-methylation,
completed the synthesis of tricyclic structure ent-16 that had
identical data to that described in the literature, except for the
sign and magnitude of the specific rotation (see Experimental
Section).21c,30
Since trans alcohol 7e was readily accessible from sulfoxide
3e in one step, we examined the application of this methodology
to access an isomeric product with a trans-fused bicyclic
structure like the core of deoxymalayamicin A. To test the
aminohydroxylation reaction with the trans substituted substrate,
we first explored the process for model substrate 7a (Scheme
16). Hydroxycarbamate 38a was prepared as described before,
and after sulfonylation afforded the required N-sulfonyloxy
precursor for the aminohydroxylation step. Under optimized
conditions, oxazolidinone 40a was obtained as a single product
with good yield. The regiochemistry of the product was again
confirmed by NOE interactions on acetate 41a.
we started the synthesis from 3-butyn-1-ol 26 and after
protection of the hydroxyl group as a TBDPS ether, alkynyl
sulfoxide 28e was formed by reaction with EtMgBr and (-)-
menthyl p-toluenesulfinate in excellent yield.
Hydrostannylation of 28e and tin-iodine exchange, led to
vinyl iodide 30e that underwent a Stille coupling with hydroxy
vinyl stannane 31 to give sulfinyl diene 1e in excellent yield.
Base-promoted cyclization with LDA afforded sulfinyl dihy-
dropyran 3e as a single isomer. The sigmatropic rearrangement
using Na2S·9H2O surprisingly led to similar results to the
TBDMS derivative (89% cis:trans, 94:6 deprotected derivatives
8g and ent-7g as seen in Table 2, entry 4). We hypothesized
that sulfenic acids formed in the sigmatropic rearrangement
could be effecting cleavage of the silyl group, but addition of
excess K2CO3 in the reaction media was not effective to avoid
desilylation. Fortunately the optimized conditions for the [2,3]-
sigmatropic rearrangement (DABCO, toluene) worked perfectly
on allylic sulfoxide 3e to produce allylic alcohol 7e that was
inverted by a Mitsunobu protocol to give 3,6-cis alcohol 8e. It
should be pointed out that, under different conditions, diene 1e
leads to allylic alcohol 8e in one or two steps (Scheme 14).
Reaction of 1e with phosphazene P2-tBu afforded the expected
product 3e, along with 2,3-cis sulfinyl dihydropyran 4e7 with
moderate selectivity, which could be easily transformed into
alcohol 8e by sigmatropic rearrangement with P(OMe)3. Cy-
clization of 1e with BEMP, afforded 3e and a considerable
amount of 8e obtaining the desired substrate in one step from
the diene with moderate selectivity.
Treatment of alcohol 8e with trichloroacetylisocyanate fol-
lowed by aqueous K2CO3 as described above for the model
substrate gave carbamate 23e in excellent yield (98%) (Scheme
15). Carbamate 23e was submitted to the original conditions
for aminohydroxylation,24a to afford a disappointing 26% yield
(30) Similar conditions to those previously used for the model substrate with
MeI, BaO, and Ba(OH)2 led to complex reaction mixtures, where only traces of
the desired product could be identified.
J. Org. Chem. Vol. 73, No. 22, 2008 8937

Ferna´ndez de la Pradilla et al.
SCHEME 15. Synthesis of ent-16
SCHEME 16. Model Substrate for the Synthesis of 18
SCHEME 17. Synthesis of 18
Once we had secured that the aminohydroxylation was
effective for the trans model substrate, we carried out the
sequence from alcohol 7e (Scheme 17). Reaction with carbo-
nyldiimidazole and hydroxylamine led to 38e that after sulfo-
nylation with mesitylsulfonyl chloride afforded aminohydrox-
ylation precursor 39e. The aminohydroxylation of 39e proceeded
smoothly to give oxazolidinone 40e as a single product.
Cleavage of the silyl group with Dowex, and selective oxidation
of the primary alcohol with TEMPO with concurrent cyclization
as observed for the cis series, led to butyrolactone 18.
Unfortunately this intermediate had limited stability and led to
ring opening degradation products upon standing for a few days
in solution in CDCl3.
tively and in moderate to excellent yields. We have applied these
conditions to the formal synthesis of ent-dysiherbaine from
commercially available 3-butyn-1-ol and from a common
intermediate of this route, a new approach to the core of
deoxymalayamicin A was explored. Thus, related structures ent-
16 and trans-fused isomer 18 were prepared from a common
precursor using a [2,3]-sigmatropic rearrangement and a tethered
aminohydroxylation as key steps.
Experimental Section
In conclusion, we have studied the [2,3]-sigmatropic rear-
rangement of allylic sulfinyl dihydropyrans, under different
conditions with various thiophilic agents. Under standard
conditions [P(OMe)3/MeOH], the products were obtained in low
yields for the less reactive substrates; the yields were better using
Et2NH or Na2S·9H2O in MeOH, but mixtures of diastereomers
were obtained. Tertiary amines in toluene and slightly higher
temperatures afforded the desired allylic alcohols stereoselec-
(+)-(Ss)-tert-Butyldiphenyl[4-(p-tolylsulfinyl)-but-3-ynyloxy]-
silane (28e). From alkyne 27e (558 mg, 1.81 mmol, 2.2 equiv),
Mg turnings (40 mg, 1.65 mmol, 2 equiv), EtBr (0.14 mL, 1.81
mmol, 2.2 equiv) and (-)-menthyl p-toluenesulfinate (242 mg,
0.823 mmol, 1 equiv), according to the general procedure described
in the Supporting Information (22 h) alkynyl sulfoxide 28e was
obtained. Purification by chromatography (5-30% EtOAc-hexane)
afforded 28e (340 mg, 0.761 mmol, 92%) as a colorless oil. Rf
8938 J. Org. Chem. Vol. 73, No. 22, 2008

[2,3]-Sigmatropic Rearrangements of 3-Sulfinyl Dihydropyrans
0.22 (20% EtOAc-hexane). [R]20D +30.4 (c ) 1.30). 1H NMR (300
MHz) δ 1.01 (s, 9 H,), 2.39 (s, 3 H), 2.65 (t, 2 H, J ) 6.6 Hz),
3.77 (t, 2 H, J ) 6.6 Hz), 7.28 (d, 2 H, J ) 8.3 Hz), 7.32-7.44
(m, 6 H), 7.61 (d, 2 H, J ) 8.0 Hz), 7.61 (d, 2 H, J ) 7.6 Hz),
7.66 (d, 2 H, J ) 8.2 Hz). 13C NMR (75 MHz) δ 19.1, 21.4, 23.8,
26.6 (3 C), 61.0, 79.1, 102.9, 125.0 (2 C), 127.7 (4 C), 129.7 (2
C), 130.1 (2 C), 133.0, 135.4 (5 C), 140.9, 142.1. IR (film): 3069,
3045, 2955, 2931, 2878, 2854, 2185, 1590, 1472, 1428, 1113, 1061,
810, 737, 703 cm-1. MS (ES): 893 [2M + 1]+, 447 [M + 1]+, 469
[M + Na]+, 369 [M - Ph]+ (100%).
4.01 (m, 1 H), 5.57 (d, 1 H, J ) 11.3 Hz), 5.99-6.10 (m, 2 H),
7.18 (d, 2 H, J ) 7.9 Hz), 7.30-7.45 (m, 8 H), 7.63-7.67 (m, 4
H). 13C NMR (75 MHz) δ 19.2, 21.3, 26.8 (3 C), 32.1, 58.1, 63.0,
121.4, 124.3, 127.8 (3 C), 129.7 (3 C), 129.8 (3 C), 133.3 (2 C),
135.5 (4 C), 137.9, 138.2, 138.3, 141.0, 142.3. IR (film): 3401,
3069, 3045, 2955, 2931, 2858, 1590, 1471, 1428, 1390, 1112, 1039,
809, 753, 703 cm-1. MS (ES): 1031 [2M + Na]+, 527 [M + Na]+
(100%), 505 [M + 1]+. Anal. calcd for C30H36O3SSi: C, 71.39; H,
7.19; S, 6.35. Found: C, 71.43; H, 7.13; S, 6.39.
(-)-(2S,3R,RS)-tert-Butyldiphenyl-{2-[3-(p-tolylsulfinyl)-3,6-di-
hydro-2H-pyran-2-yl]-ethoxy}silane (3e), and (2S,3S,RS)-tert-Bu-
tyldiphenyl-{2-[3-(p-tolylsulfinyl)-3,6-dihydro-2H-pyran-2-yl]-
ethoxy}silane (4e). From dienyl sulfoxide 1e (37 mg, 0.073 mmol)
and P2-tBu (40 µL, 0.08 mmol, 1.1 equiv) according to the general
procedure D described in the Supporting Information (3 min), a
65:35 mixture of dihydropyrans 4e and 3e was obtained. Purification
by chromatography (0-10% Et2O-CH2Cl2) afforded 3e (15 mg,
0.030 mmol, 41%) and 4e (19 mg, 0.038 mmol, 52%) as colorless
oils. Allylic sulfoxide 4e was unstable; rapid sigmatropic rear-
rangement occurred to produce alcohol 8e, and this prevented the
complete characterization of the sulfoxide.
(-)-(S,E)-tert-Butyldiphenyl[4-(p-tolylsulfinyl)-4-(tributylstannyl)-
but-3-enyloxy]silane (29e). From alkynyl sulfoxide 28e (884 mg,
1.98 mmol), Bu3SnH (0.6 mL, 2.2 mmol, 1.1 equiv) and Pd(Ph3P)4
(46 mg, 0.04 mmol, 0.02 equiv), according to the general procedure
described in the Supporting Information (15 h) a 90:10 mixture of
stannanes 29e and 29e′ was obtained. Purification by chromatog-
raphy (2-20% EtOAc-hexane) afforded 29e (1.22 g, 1.65 mmol,
83%) and 29e′ (127 mg, 0.172 mmol, 9%) as colorless oils.
Data for 29e: Rf 0.26 (10% EtOAc-hexane). [R]20D -38.9 (c )
0.84). 1H NMR (300 MHz) δ 0.80-1.01 (m, 15 H), 1.05 (s, 9 H),
1.13-1.52 (m, 12 H), 2.35 (s, 3 H), 2.66 (m, 1 H), 2.90 (m, 1 H),
3.78 (t, 2 H, J ) 6.1 Hz), 6.38 (dd, 1 H, J ) 7.6, 6.3 Hz), 7.18 (d,
2 H, J ) 8.1 Hz), 7.34-7.44 (m, 8 H), 7.65 (d, 4 H, J ) 7.6 Hz).
13C NMR (75 MHz) δ 11.3 (3 C), 13.6 (3 C), 19.2, 21.2, 26.8 (3
C), 27.2 (3 C), 28.7 (3 C), 35.8, 62.7, 124.4, 127.7 (2 C), 129.5 (3
C), 129.7 (4 C), 133.4, 133.5, 135.5 (4 C), 139.9, 142.3, 145.6,
157.8. IR (film): 3069, 3045, 2956, 2928, 2857, 1587, 1488, 1463,
1428, 1378, 1112, 1039, 942, 822, 805, 736, 702 cm-1. MS (ES):
Data for 3e: Rf 0.16 (30% EtOAc-hexane). [R]20D -109.9 (c )
1
0.95). H NMR (300 MHz) δ 1.03 (s, 9 H), 1.93 (q, 2 H, J ) 6.6
Hz), 2.31 (s, 3 H), 3.27 (ap t, 1 H, J ) 1.0 Hz), 3.77 (dd, 1 H, J
) 10.0, 5.4 Hz), 3.84 (dt, 1 H, J ) 10.4, 7.0 Hz), 3.95 (ap d, 2 H,
J ) 2.2 Hz), 4.35 (m, 1 H), 5.30 (ddd, 1 H, J ) 10.5, 4.6, 2.4 Hz),
5.90 (ap d, 1 H, J ) 10.3 Hz), 7.23 (d, 2 H, J ) 8.3 Hz), 7.32-7.44
(m, 6 H), 7.51 (d, 2 H, J ) 8.1 Hz), 7.63-7.67 (m, 4 H). 13C
NMR (75 MHz) δ 19.2, 21.5, 26.8 (3 C), 34.3, 61.5, 65.4 (2 C),
67.6, 116.6, 125.5 (2 C), 127.7 (4 C), 129.6 (4 C), 132.2, 133.5,
133.6, 135.6 (4 C), 138.3, 142.0. IR (film) 3069, 3047, 2955, 2930,
2859, 1590, 1493, 1472, 1428, 1390, 1261, 1186, 1112, 1084, 1047,
940, 812, 738, 703 cm-1. MS (ES): 1031 [2M + Na]+, 527 [M +
Na]+ (100%), 505 [M + 1]+.
t
761 [M + Na]+, 681 [M - Bu]+ (100%).
Data for (-)-(R,E)-tert-Butyldiphenyl[4-(p-tolylsulfinyl)-3-(tribu-
tylstannyl)but-3-enyloxy]silane, 29e′: Rf 0.10 (10% EtOAc-hexane).
1
[R]20 -63.3 (c ) 1.40). H NMR (300 MHz) δ 0.80 (m, 15 H),
D
1.06 (s, 9 H), 1.11-1.38 (m, 12 H), 2.35 (s, 3 H), 3.04 (m, 2 H),
3.60 (td, 1 H, J ) 9.5, 6.2 Hz), 3.73 (td, 1 H, J ) 9.5, 6.2 Hz),
6.18 (s, 1 H), 7.18 (d, 2 H, J ) 8.3 Hz), 7.34-7.44 (m, 8 H),
7.64-7.70 (m, 4 H). 13C NMR (75 MHz) δ 10.1 (3 C), 13.5 (3 C),
19.2, 21.3, 26.8 (3 C), 27.1 (2 C), 28.6 (3 C), 28.8, 39.0, 63.3,
124.2, 127.7 (4 C), 129.7 (2 C), 129.8 (2 C), 133.5, 135.5 (3 C),
135.6 (3 C), 140.6, 141.9, 145.5, 155.8. IR (film): 3069, 3045, 2957,
2929, 2857, 1590, 1492, 1464, 1428, 1378, 1111, 1081, 1043, 822,
808, 739, 702 cm-1. MS (ES): 761 [M + Na]+ (100%).
Partial Data for 4e: Rf 0.33 (20% EtOAc-CH2Cl2). 1H NMR (300
MHz) δ 1.04 (s, 9 H), 2.09-2.20 (m, 1 H), 2.33-2.42 (m, 1 H),
2.39 (s, 3 H), 2.95 (dt, 1 H, J ) 5.6, 2.8 Hz), 3.86 (quint, 1 H, J
) 5.1 Hz), 3.98 (ddd, 1 H, J ) 10.2, 8.5, 4.6 Hz), 4.13 (dm, 1 H,
J ) 17.3 Hz), 4.19 (m, 1 H), 4.34 (dm, 1 H, J ) 17.3 Hz), 5.33
(m, 1 H), 6.23 (ddd, 1 H, J ) 11.9, 2.8, 1.5 Hz), 7.27-7.35 (m, 3
H), 7.36-7.42 (m, 7 H), 7.63-7.68 (m, 4 H). 13C NMR (75 MHz)
δ 19.2, 21.3, 26.9 (3 C), 36.0, 60.0, 64.1, 66.2, 71.5, 115.7, 124.1
(2 C), 127.7 (3 C), 129.6 (2 C), 129.7 (3 C), 133.6, 133.8, 135.0,
135.5 (4 C), 139.5, 140.8. MS (ES): 1031 [2M + Na]+, 527 [M +
Na]+ (100%), 505 [M + 1]+.
(-)-(S,E)-tert-Butyl[4-iodo-4-(p-tolylsulfinyl)but-3-enyloxy]di-
phenylsilane (30e). From stannane 29e (1.22 g, 1.65 mmol) and
iodine (502 mg, 1.98 mmol, 1.2 equiv), according to the general
procedure described in the Supporting Information (1 h 30 min)
iodide 30e was obtained. Purification by chromatography (5-20%
EtOAc-hexane) afforded 30e (814 mg, 1.42 mmol, 86%) as a
colorless oil. Rf 0.38 (30% EtOAc-hexane). [R]20D -51.0 (c ) 0.67).
1H NMR (300 MHz) δ 1.07 (s, 9 H), 2.36 (s, 3 H), 2.92 (m, 2 H),
3.82 (t, 2 H, J ) 6.2 Hz), 6.93 (t, 1 H, J ) 7.7 Hz), 7.19 (d, 2 H,
J ) 8.1 Hz), 7.36-7.46 (m, 8 H), 7.63-7-67 (m, 4 H). 13C NMR
(75 MHz) δ 19.0, 21.3, 26.7 (3 C), 36.4, 62.1, 115.8, 124.2 (2 C),
127.7 (4 C), 129.6 (2 C), 129.7, 132.9, 133.0, 135.3 (5 C), 139.6,
141.4, 148.7. IR (film): 3069, 3045, 2955, 2930, 2858, 1590, 1491,
1472, 1428, 1390, 1111, 1089, 942, 819, 810, 703 cm-1. MS (ES):
1171 [2M + Na]+, 597 [M + Na]+ (100%), 497 [M - Ph]+. Anal.
calcd for C27H31IO2SSi: C, 56.44; H, 5.44; I, 22.09; S, 5.58. Found:
C, 56.36; H, 5.58; I, 21.96; S, 5.56.
(-)-(S)-2-(Z)-4-(Z)-7-(tert-Butyldiphenylsilyloxy)-4-(p-tolylsulf-
inyl)hepta-2,4-dien-1-ol (1e). From iodide 30e (801 mg, 1.39 mmol),
stannane 31 (1.2 equiv, 828 mg of 70:30 mixture 31 and 31′, 1.67
mmol 31), BHT (306 mg, 1.39 mmol), Ph3As (85 mg, 0.278 mmol)
and Pd2(dba)3 ·CHCl3 (72 mg, 0.07 mmol), according to the general
procedure described in the Supporting Information (21 h), diene
1e was obtained as a single isomer. Purification by chromatography
(15-50% EtOAc-hexane) afforded 1e (662 mg, 1.31 mmol, 94%)
as a colorless oil. Rf 0.17 (50% EtOAc-hexane). [R]20D -34.8 (c )
0.71). 1H NMR (300 MHz) δ 1.06 (s, 9 H), 2.36 (s, 3 H), 2.57 (dd,
1 H, J ) 8.5, 4.7 Hz), 2.92 (ap q, 2 H, J ) 6.8 Hz), 3.82 (m, 3 H),
(+)-(3S,6S)-6-[2-(tert-Butyldiphenylsilyloxy)ethyl]-3,6-dihydro-
2H-pyran-3-ol (7e). From sulfoxide 3e (114 mg, 0.226 mmol) and
DABCO (30 mg, 0.271 mmol, 2 equiv), according to the general
procedure H described in the Supporting Information (17 h) alcohol
7e was obtained. Purification by chromatography (0-15% EtOAc-
CH2Cl2) afforded 7e (80 mg, 0.209 mmol, 93%) as a colorless oil.
1
Rf 0.25 (15% EtOAc-CH2Cl2). [R]20 +35.8 (c ) 1.20). H NMR
D
(300 MHz) δ 1.03 (s, 9 H), 1.64 (d, 1 H, J ) 8.3 Hz), 1.74 (ap q,
2 H, J ) 6.0 Hz), 3.41 (dd, 1 H, J ) 11.2, 6.3 Hz), 3.73 (quint, 1
H, J ) 5.6 Hz), 3.82 (dt, 1 H, J ) 10.4, 7.0 Hz), 3.95 (dd, 1 H, J
) 11.3, 4.5 Hz), 4.11 (br s, 1 H), 4.31 (tm, 1 H, J ) 7.5 Hz), 5.79
(ddd, 1 H, J ) 11.2, 1.9, 1.0 Hz), 5.85 (dt, 1 H, J ) 10.3, 2.2 Hz),
7.33-7.44 (m, 6 H), 7.61-7.68 (m, 4 H). 13C NMR (100 MHz),
HSQC δ 19.2 (tBu), 26.8 (3 C, tBu), 36.6 (CH2CH2OTBDPS), 60.1
(CH2OTBDPS), 62.9 (C-6), 68.1 (C-2), 70.4 (C-3), 127.6 (4 C),
127.7 (C-5), 129.6, 132.9, 133.7 (C-4), 133.8, 135.5 (3 C), 135.6
(2 C). IR (film): 3383, 3068, 3045, 2955, 2930, 2855, 1471, 1428,
1184, 1112, 1086, 823, 734, 702 cm-1. MS (ES): 405 [M + Na]+
(100%), 383 [M + 1]+. Anal. calcd for C23H30O3Si: C, 72.21; H,
7.90. Found: C, 72.26; H, 8.02.
(-)-(3R,6S)-6-[2-(tert-Butyldiphenylsilyloxy)ethyl]-3,6-dihydro-
2H-pyran-3-ol (8e). From sulfoxide 4e (19 mg, 0.038 mmol) and
P(OMe)3 (45 µL, 0.54 mmol, 10 equiv), according to the general
procedure A described in the Supporting Information (4 h) alcohol
J. Org. Chem. Vol. 73, No. 22, 2008 8939

Ferna´ndez de la Pradilla et al.
8e was obtained. Purification by chromatography (0-15% EtOAc-
CH2Cl2) afforded 8e (12 mg, 0.031 mmol, 83%) as a colorless oil.
From alcohol 7e (364 mg, 0.951 mmol), PPh3 (748 mg, 2.85
mmol, 3 equiv), p-nitrobenzoic acid (476 mg, 2.85 mmol, 3 equiv),
and DIAD (0.55 mL, 2.85 mmol, 3 equiv), according to the general
Mitsunobu procedure B described in the Supporting Information
(1 h 30 min), ester 8e′ was obtained. Purification by chromatography
(5-20% EtOAc-hexane) afforded impure 8e′ (640 mg, 0.951 mmol,
100%) as a yellow oil. From impure ester 8e′ and K2CO3 (263 mg,
1.90 mmol) according to the general procedure (1 h 30 min), alcohol
8e was obtained. Purification by chromatography (0-10% EtOAc-
carbamate 32e (94 mg, 0.213 mmol), mesitylsulfonyl chloride (47
mg, 0.213 mmol) and Et3N (89 µL, 0.639 mmol, 3 equiv), according
to the general procedure described in the Supporting Information
(30 min) 33e was obtained. Purification by chromatography
(5-20% EtOAc-hexane) afforded 33e (117 mg, 0.188 mmol, 88%)
as a colorless oil. Rf 0.23 (20% EtOAc-hexane). [R]20D -41.9 (c )
0.98). 1H NMR (300 MHz) δ 1.03 (s, 9 H), 1.77 (m, 2 H), 2.28 (s,
3 H), 2.64 (s, 6 H), 3.59 (dd, 1 H, J ) 13.2, 2.7 Hz), 3.72-3.89
(m, 3 H), 4.18 (m, 1 H), 4.81 (d, 1 H, J ) 2.2 Hz), 5.71 (dd, 1 H,
J ) 10.2, 5.0 Hz), 5.98 (d, 1 H, J ) 10.3 Hz), 6.94 (s, 2 H),
7.33-7.41 (m, 6 H), 7.64 (m, 4 H), 7.83 (d, 1 H, J ) 3.7 Hz). 13
C
NMR (75 MHz) δ 19.2, 21.1, 22.9 (2 C), 26.8 (3 C), 37.5, 59.8,
67.2, 67.6, 70.8, 120.9, 127.6 (5 C), 128.2, 129.6 (2 C), 131.7,
133.6, 133.7, 135.5 (5 C), 137.7, 142.0, 144.4, 155.1. IR (film):
3220, 3065, 3047, 2931, 2884, 2857, 1769, 1603, 1472, 1428, 1373,
1232, 1193, 1180, 1111, 1028, 824, 740, 704 cm-1. MS (ES): 646
[M + Na]+ (100%).
CH2Cl2) afforded 8e (293 mg, 0.766 mmol, 81%) as a colorless
1
oil. Rf 0.37 (20% EtOAc-CH2Cl2). [R]20 -39.8 (c ) 1.07). H
D
NMR (300 MHz) δ 1.04 (s, 9 H), 1.70-1.86 (m, 2 H), 2.33 (d, 1
H, J ) 2.0 Hz), 3.64 (dd, 1 H, J ) 12.0, 2.2 Hz), 3.78 (ap q, 1 H,
J ) 5.4 Hz), 3.85 (m, 2 H, H-6), 3.92 (dt, 1 H, J ) 12.0, 1.3 Hz),
4.21 (ap td, 1 H, J ) 7.3, 1.7 Hz), 5.85 (dd, 1 H, J ) 10.1, 1.3
Hz), 5.95 (ddt, 1 H, J ) 10.0, 4.9, 1.7 Hz), 7.33-7.44 (m, 6 H),
7.66 (m, 4 H). 13C NMR (75 MHz) δ 19.2, 26.8 (3 C), 37.9, 60.0,
62.6, 70.7, 71.4, 126.4, 127.6 (4 C), 129.6 (2 C), 133.8, 133.9,
134.5, 135.6 (4 C). IR (film): 3391, 3069, 3045, 3009, 2955, 2930,
(-)-(3aR,6S,7S,7aR)-6-(2-(tert-Butyldiphenylsilyloxy)ethyl)-7-hy-
droxytetrahydro-1H-pyrano[4,3-d]oxazol-2(6H)-one (24e). From
carbamate 23e (30 mg, 0.070 mmol), NaOH (0.8 mL, 0.08 M, 0.063
t
i
mmol, 0.9 equiv), BuOCl (8 mg, 0.070 mmol, 1 equiv), Pr2NEt
(5 µL, 0.004 mmol, 0.05 equiv) and K2OsO2(OH)4 (2 mg, 0.006
mmol, 0.08 equiv) according to general procedure M described in
the Supporting Information (25 h), 24e was obtained. Purification
by chromatography (0-50% EtOAc-CH2Cl2) afforded 24e (8 mg,
0.018 mmol, 26%) as a colorless oil and 34e (8 mg, 0.018 mmol,
26%) as a white solid, along with recovered starting material (14
mg, 0.033 mmol, 48%).
2854, 1471, 1428, 1259, 1112, 1090, 1028, 822, 804, 758, 702 cm-1
.
MS (ES): 405 [M + Na]+ (100%).
(-)-(3R,6S)-6-[2-(tert-Butyldiphenylsilyloxy)ethyl]-3,6-dihydro-
2H-pyran-3-yl carbamate (23e). From alcohol 8e (25 mg, 0.065
mmol), trichloroacetyl isocyanate (10 µL, 0.078 mmol, 1.2 equiv),
and K2CO3 (aq) (0.1 mL, 0.195 mmol, 3 equiv), according to
general procedure K described in the Supporting Information (5 h
30 min), carbamate 23e was obtained. Purification by chromatog-
raphy (5-20% EtOAc-CH2Cl2) afforded 23e (27 mg, 0.063 mmol,
From carbamate 33e (110 mg, 0.176 mmol), iPr2NEt (5 µL, 0.009
mmol, 0.05 equiv) and K2OsO2(OH)4 (4 mg, 0.011 mmol, 0.06
equiv) according to general procedure L described in the Supporting
Information (4 h), 24e was obtained. Purification by chromatography
(0-50% EtOAc-CH2Cl2) afforded 24e (60 mg, 0.136 mmol, 77%)
as a colorless oil.
98%) as a white solid. Rf 0.32 (20% EtOAc-CH2Cl2). mp 103-105
1
°C. [R]20 -64.3 (c ) 1.02). H NMR (300 MHz), COSY δ 1.03
D
t
(s, 9 H, Bu), 1.80 (q, 2 H, J ) 5.4 Hz, CH2CH2OTBDPS), 3.70
(dd, 1 H, J ) 13.1, 2.5 Hz, H-2), 3.78 (ap dd, 1 H, J ) 10.3, 5.3
Hz, CH2OTBDPS), 3.87 (dt, 1 H, J ) 10.5, 6.7 Hz, CH2OTBDPS),
4.03 (d, 1 H, J ) 13.0 Hz, H-2), 4.22 (m, 1 H, H-6), 4.64 (br s, 2
H, NH2), 4.91 (m, 1 H, H-3), 5.91 (dm, 1 H, J ) 10.4 Hz, H-4),
5.99 (d, 1 H, J ) 10.4 Hz, H-5), 7.33-7.43 (m, 6 H, Ar-H), 7.64
(m, 4 H, Ar-H). 13C NMR (75 MHz) δ 19.2, 26.8 (3 C), 37.7,
59.9, 65.3, 68.1, 70.9, 122.2, 127.6 (3 C), 129.6, 133.7, 133.8, 135.5
(3 C), 135.6 (3 C), 136.7, 156.3 (CdO). IR (KBr): 3463, 3385,
3350, 3069, 2955, 2931, 2857, 1716, 1590, 1428, 1387, 1308, 1112,
1036, 823, 757, 702 cm-1. MS (ES): 448 [M + Na]+ (100%). Anal.
calcd for C24H31SiNO4: C, 67.73; H, 7.34; N, 3.29. Found: C, 67.81;
H, 7.18, N, 3.41.
Data for 24e: Rf 0.21 (50% EtOAc-CH2Cl2). [R]20 -8.7 (c )
D
1
t
0.85). H NMR (300 MHz), COSY δ 1.02 (s, 9 H, Bu), 1.73 (m,
1 H, CH2CH2OTBDPS), 1.91 (m, 1 H, CH2CH2OTBDPS), 3.22
(d, 1 H, J ) 8.7 Hz, OH), 3.45 (dd, 1 H, J ) 8.6, 4.4 Hz, H-6),
3.55-3.66 (m, 3 H, H-4, H-7, H-7a), 3.72, (q, 1 H, J ) 5.0 Hz,
CH2OTBDPS), 3.80 (m, 1 H, CH2OTBDPS), 4.27 (d, 1 H, J )
14.3 Hz, H-4), 4.39 (dd, 1 H, J ) 6.1, 2.3 Hz, H-3a), 6.30 (br s, 1
H, NH), 7.32-7.42 (m, 6 H, Ar-H), 7.59-7.63 (m, 4 H, Ar-H).
NOESY-2D CH2CH2OTBDPS/OH. 13C NMR (75 MHz), HSQC,
DEPT δ 19.2 (tBu), 26.9 (3 C, tBu), 34.2 (CH2CH2OTBDPS), 54.2
(C-7), 59.7 (CH2OTBDPS), 66.6 (C-4), 66.9 (C-7a), 73.5 (C-3a,
C-6), 127.7 (4 C), 129.7 (2 C), 133.6, 135.5 (5 C), 161.7 (C-2). IR
(CHCl3): 3414, 3068, 3045, 2955, 2930, 2857, 1749, 1630, 1428,
1390, 1213, 1112, 1089, 1014, 953, 824, 703 cm-1. MS (ES): 464
[M + Na]+ (100%). Anal. calcd for C24H31NO5Si: C, 65.28; H,
7.08; N, 3.17. Found: C, 65.42; H, 7.24; N, 3.05.
(-)-(3R,6S)-6-(2-(tert-Butyldiphenylsilyloxy)ethyl)-3,6-dihydro-
2H-pyran-3-yl hydroxycarbamate (32e). From alcohol 8e (56 mg,
0.146 mmol), N,N′-carbonyldiimidazole (71 mg, 0.438 mmol, 3
equiv), imidazole (40 mg, 0.584 mmol, 4 equiv) and hydroxylamine
hydrochloride (51 mg, 0.73 mmol, 5 equiv), according to general
procedure L described in the Supporting Information (17 h),
hydroxy carbamate 32e was obtained. Purification by chromatog-
raphy (0-20% EtOAc-CH2Cl2) afforded 32e (55 mg, 0.125 mmol,
86%) as a colorless oil. Rf 0.18 (15% EtOAc-CH2Cl2). [R]20D -47.9
(c ) 0.39). 1H NMR (300 MHz), COSY δ 1.03 (s, 9 H, tBu), 1.76
(m, 3 H, CH2CH2OTBDPS, OH), 3.70 (dd, 1 H, J ) 13.0, 2.3 Hz,
H-2), 3.76 (dd, 1 H, J ) 10.4, 5.2 Hz, CH2OTBDPS), 3.85 (dt, 1
H, J ) 10.3, 6.7 Hz, CH2OTBDPS), 4.03 (d, 1 H, J ) 13.2 Hz,
H-2), 4.23 (m, 1 H, H-6), 4.97 (m, 1 H, H-3), 5.89 (dd, 1 H, J )
10.2, 4.7 Hz, H-4), 6.00 (d, 1 H, J ) 10.4 Hz, H-5), 6.79 (br s 1
H, NH), 7.30-7.43 (m, 6 H, Ar-H), 7.64 (m, 4 H, Ar-H). 13C
NMR (75 MHz) δ 19.2, 26.8 (3 C), 37.6, 59.8, 66.5, 67.8, 71.0,
121.6, 127.6 (4 C), 129.6 (2 C), 133.7, 133.8, 135.6 (4 C), 137.2,
158.7. IR (film): 3306, 3069, 3045, 2955, 2931, 2854, 1723, 1471,
1428, 1262, 1112, 1028, 822, 801, 739, 702 cm-1. MS (ES): 464
[M + Na]+ (100%). Anal. calcd for C24H31SiNO5: C, 65.28; H,
7.08; N, 3.17. Found: C, 65.44; H, 7.18, N, 3.31.
Data for (+)-(3aS,4S,7R,7aS)-4-(2-(tert-Butyldiphenylsilyloxy)-
ethyl)-7-hydroxytetrahydro-1H-pyrano[4,3-d]oxazol-2(6H)-one, 34e:
Rf 0.10 (50% EtOAc-CH2Cl2). mp 155-157 °C. [R]20 +27.7 (c
D
t
1
) 0.61). H NMR (300 MHz), COSY δ 1.03 (s, 9 H, Bu), 1.90
(ddt, 1 H, J ) 13.7, 9.1, 4.7 Hz, CH2CH2OTBDPS), 2.01 (ddd, 1
H, J ) 13.1, 9.2, 4.5 Hz, CH2CH2OTBDPS), 2.79 (d, 1 H, J ) 9.3
Hz, OH), 3.36 (d, 1 H, J ) 12.5 Hz, H-6), 3.63-3.85 (m, 4 H,
H-7, H-4, H-7a, CH2OTBDPS), 3.89 (dd, 1 H, J ) 10.4, 4.3 Hz,
CH2OTBDPS), 3.99 (dd, 1 H, J ) 12.2, 2.4 Hz, H-6), 4.30 (dd, 1
H, J ) 6.0, 2.1 Hz, H-3a), 5.77 (br s, 1 H, NH), 7.24-7.44 (m, 6
H, Ar-H), 7.61-7.65 (m, 4 H, Ar-H). 13C NMR (75 MHz) δ
19.2, 26.9 (3 C), 33.9, 53.8, 59.5, 64.8, 68.8, 72.6, 75.7, 127.7 (4
C), 129.7 (2 C), 133.6, 135.5 (4 C), 161.1. IR (CHCl3): 3367, 2955,
2925, 2854, 1717, 1646, 1447, 1428, 1248, 1093, 834 cm-1. MS
(ES): 464 [M + Na]+ (100%).
(-)-(3aR,6S,7S,7aR)-7-Hydroxy-6-(2-hydroxyethyl)tetrahydro-
1H-pyrano[4,3-d]oxazol-2(6H)-one (35e). From oxazolone 24e (100
mg, 0.226 mmol) and DOWEX (113 mg, 0.5 g/mmol) according
to the general procedure described in the Supporting Information
(-)-(3R,6S)-6-(2-(tert-Butyldiphenylsilyloxy)ethyl)-3,6-dihydro-
2H-pyran-3-yl mesitylsulfonyloxycarbamate (33e). From hydroxy
8940 J. Org. Chem. Vol. 73, No. 22, 2008

[2,3]-Sigmatropic Rearrangements of 3-Sulfinyl Dihydropyrans
(3 days), alcohol 35e was obtained. Purification by chromatography
(0-30% MeOH-CH2Cl2) afforded 35e (33 mg, 0.162 mmol, 72%)
mmol, 2 equiv) and the solution was stirred for 5 min. A solution
of substrate 36e (16 mg, 0.080 mmol, 1 equiv) in THF-DMF (1:
1) (0.4 mL, 5 mL/mmol substrate) was added and the reaction was
stirred at -40 °C for 5 h and then warmed to rt. When no more
evolution was observed (TLC) the reaction was quenched with
saturated NH4Cl (4 mL/mmol) solution and H2O (4 mL/mmol),
and diluted with EtOAc. The layers were separated and the aqueous
layer was extracted with EtOAc (3 × 4 mL/mmol). The combined
organic layers were washed with brine (3 mL/mmol), dried over
MgSO4, filtered and concentrated under reduced pressure. Purifica-
tion by chromatography (0-10% MeOH-CH2Cl2) afforded ent-16
(10 mg, 0.047 mmol, 59%) as a white solid that was recrystallized
from CH2Cl2-Et2O along with recovered starting material (3 mg,
0.015 mmol, 19%). Rf 0.39 (10% MeOH-CH2Cl2). mp 185-186
as a white solid. Rf 0.28 (20% MeOH-CH2Cl2). mp 144-146 °C.
1
[R]20 -15.0 (c ) 0.16 acetone). H NMR (500 MHz, CD3OD),
D
COSY δ 1.61 (dtd, 1 H, J ) 14.2, 7.1, 4.4 Hz, CH2CH2OH), 1.87
(ddt, 1 H, J ) 14.3, 8.9, 5.4 Hz, CH2CH2OH), 3.36 (ddd, 1 H, J )
8.9, 4.3, 0.7 Hz, H-6), 3.49 (d, 1 H, J ) 4.6 Hz, H-7), 3.59 (dd, 2
H, J ) 7.1, 5.4 Hz, CH2OH), 3.70 (dd, 1 H, J ) 14.2, 2.9 Hz,
H-4), 3.72 (dd, 1 H, J ) 6.4, 4.7 Hz, H-7a), 4.18 (d, 1 H, J ) 14.2
Hz, H-4), 4.36 (dd, 1 H, J ) 6.6, 2.7 Hz, H-3a), 4.50 (s, 3 H, NH,
2 OH). 13C NMR (75 MHz, CD3OD) δ 35.6, 55.0, 59.3, 67.4, 67.6,
74.9, 75.4, 163.9. IR (CCl4): 3402, 2960, 2927, 2854, 1739, 1656,
1583, 1550, 1442, 1257, 1239, 1214, 1154, 1093, 1048, 973 cm-1
.
MS (ES): 226 [M + Na]+ (100%), 204 [M + 1]+. Anal. calcd for
C8H13NO5: C, 47.29; H, 6.45; N, 6.89. Found: C, 47.37; H, 6.53;
N, 7.02.
°C. [R]20 -91.8 (c ) 0.40 MeOH). (Lit. for 16 +39.3 (c ) 0.41
D
1
MeOH). H NMR (300 MHz), COSY δ 2.69 (dd, 1 H, J ) 17.8,
(-)-(3aR,5aS,8aS,8bS)-Hexahydro-2H-furo[2′,3′:5,6]pyrano[4,3-d]-
[1,3]oxazole-2,7(1H)-dione (36e). From alcohol 35e (11 mg, 0.054
mmol), TEMPO (4 mg, 0.022 mmol, 0.4 equiv) and bis(acetoxy)-
iodobenzene (71 mg, 0.216 mmol, 4 equiv) according to the general
procedure described in the Supporting Information (22 h), 36e was
obtained. Purification by chromatography (0-20% MeOH-CH2Cl2)
afforded 36e (9 mg, 0.045 mmol, 84%) as a white solid. Rf 0.34
1.9 Hz, H-6), 2.79 (dd, 1 H, J ) 17.8, 4.9 Hz, H-6), 2.97 (s, 3 H,
Me), 3.71 (dd, 1 H, J ) 13.9, 2.9 Hz, H-4), 3.97 (dd, 1 H, J ) 7.5,
5.5 Hz, H-8b), 4.17 (dd, 1 H, J ) 13.9, 2.2 Hz, H-4), 4.33 (ddd, 1
H, J ) 5.0, 3.3, 1.7 Hz, H-5a), 4.46 (dt, 1 H, J ) 7.5, 2.7 Hz,
H-3a), 4.58 (dd, 1 H, J ) 5.4, 3.2 Hz, H-8a). 13C NMR (100 MHz,
D2O) δ 30.3, 38.7, 54.2, 64.3, 71.4, 73.6, 76.0, 161.7, 179.1. IR
(KBr): 2941, 1791, 1754, 1439, 1228, 1170, 1115, 1032, 913 cm-1
.
(20% MeOH-CH2Cl2). mp 177-179 °C. [R]20 -70.1 (c ) 0.71
MS (ES): 268 [M + Na + MeOH]+ (100%), 236 [M + Na]+, 214
[M + 1]+. Anal. calcd for C9H11NO5: C, 50.70; H, 5.20; N, 6.57.
Found: C, 50.82; H, 5.34; N, 6.61.
D
acetone). 1H NMR (300 MHz, CD3OD), COSY δ 2.48 (dd, 1 H, J
) 17.6, 2.4 Hz, H-6), 2.85 (dd, 1 H, J ) 17.6, 5.6 Hz, H-6), 3.64
(dd, 1 H, J ) 14.0, 2.1 Hz, H-4), 4.02 (dd, 1 H, J ) 13.9, 1.2 Hz,
H-4), 4.18 (dd, 1 H, J ) 7.7, 5.8 Hz, H-8b), 4.32 (ddd, 1 H, J )
6.0, 3.7, 2.3 Hz, H-5a), 4.51 (dd, 1 H, J ) 5.8, 3.8 Hz, H-8a), 4.53
(ddd, 1 H, J ) 8.2, 2.1, 1.3 Hz, H-3a). 13C NMR (125 MHz), HSQC
δ 38.2 (C-6), 50.5 (C-8b), 65.7 (C-4), 73.5 (C-5a), 73.6 (C-3a),
76.4 (C-8a), 162.4 (C-2), 176.6 (C-7). IR (KBr): 3444, 3313, 2926,
1789, 1752, 1725, 1634, 1384, 1231, 1166, 1131, 1094, 1061, 1032,
964, 915 cm-1. MS (ES): 254 [M + Na + MeOH]+ (100%), 232
[M + 1 + MeOH]+, 222 [M + Na]+, 200 [M + 1]+.
Acknowledgment. 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 doctoral fellowships to N.L., M.T., and M.A.A.
Supporting Information Available: Experimental details and
spectral data (1H NMR and 13C NMR) for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(-)-(3aR,5aS,8aS,8bS)-1-Methylhexahydro-2H-furo[2′,3′:5,6]pyr-
ano[4,3-d][1,3]oxazole-2,7(1H)-dione (ent-16). To a cold suspension
(-40 °C) of NaH (2 mg, 0.080 mmol, 1 equiv) in THF-DMF (1:1)
(0.8 mL, 10 mL/mmol substrate) MeI was added (10 µL, 0.16
JO8015709
J. Org. Chem. Vol. 73, No. 22, 2008 8941