Highly diastereoselective Katsuki-Jacobsen oxidation-epoxidation of α-silyloxy sulfinyl dienes: Synthetic applications

Article abstract of DOI:10.1021/jo801803m

(Chemical Equation Presented) Katsuki-Jacobsen oxidation-epoxidation of acyclic α-silyloxy sulfinyl dienes, followed by acid-promoted cyclization, leads to 2,5-trans-sulfonyl dihydrofurans with good selectivities. As an application, the formal syntheses of (6S,7S,9R,10R)- and (6S,7S,9S,10S)-6,9- epoxynonadec-18-ene-7,10-diols is reported.

Full text of DOI:10.1021/jo801803m

Highly Diastereoselective Katsuki-Jacobsen Oxidation-Epoxidation
of r-Silyloxy Sulfinyl Dienes: Synthetic Applications
Roberto Ferna´ndez de la Pradilla,* Alejandro Castellanos, In˜aki Osante, Ignacio Colomer,
and Mateo I. Sa´nchez
Instituto de Qu´ımica Orga´nica, CSIC, Juan de la CierVa 3, E-28006 Madrid, Spain
iqofp19@iqog.csic.es
ReceiVed August 12, 2008
Katsuki-Jacobsen oxidation-epoxidation of acyclic R-silyloxy sulfinyl dienes, followed by acid-promoted
cyclization, leads to 2,5-trans-sulfonyl dihydrofurans with good selectivities. As an application, the formal
syntheses of (6S,7S,9R,10R)- and (6S,7S,9S,10S)-6,9-epoxynonadec-18-ene-7,10-diols is reported.
SCHEME 1. Preparation of Starting Materials and Sulfonyl
Dihydrofurans (S ) SO2p-Tol)
Introduction
The catalytic asymmetric epoxidation of CdC double bonds
is one of the most powerful transformations known to organic
chemists and plays an important role in the synthesis of optically
active organic compounds. Indeed, since the invention of the
Sharpless asymmetric epoxidation,1 there has been an increasing
demand for catalyst-controlled processes that allow efficient and
predictable access to enantioenriched oxiranes. Katsuki and
Jacobsen described in the early 1990s their efficient catalytic
procedures using metal-ligated systems for the electrophilic
delivery of oxygen.2 Since then, the use of Mn-salen complexes
has been proven to be a general and efficient method for the
enantioselective epoxidation of not just unfunctionalized olefins
but also more complex dienes and enynes.3 Herein, we report
in full our results on the Katsuki-Jacobsen epoxidation of a
variety of R-hydroxy dienyl sulfoxides and derivatives as part
of our studies on the stereoselective synthesis of oxiranes and
its application to the construction of densely functionalized
tetrahydrofurans.
In recent years, we have been studying in depth the nucleo-
philic and electrophilic epoxidation of R-hydroxy dienyl sul-
(1) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976.
(2) (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801–2803. (b) Irie, R.; Noda, K.; Ito, Y.; Masumoto,
N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345–7348. For reviews, see: (c)
Katsuki, T. Synlett 2003, 3, 281–297. (d) McGarrigle, E. M.; Gilheany, D. G.
Chem. ReV. 2005, 105, 1563–1602.
(3) (a) Lee, N. H.; Jacobsen, E. N. Tetrahedron Lett. 1991, 32, 6533–6536.
(b) Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem. 1993, 58, 6939–6941.
(c) Nishikori, H.; Ohta, C.; Katsuki, T. Synlett 2000, 1557–1560.
foxides as versatile routes to highly functionalized sulfinyl and
sulfonyl tetrahydrofurans.4 Scheme 1 shows an outline of our
strategy that entails lithiation of the mixture of dienes 1E/Z5
and condensation with freshly distilled aldehydes, followed by
chromatographic separation, to afford dienols 2 and 3.6 These
diastereomers were interconverted by a Mitsunobu protocol. The
170 J. Org. Chem. 2009, 74, 170–181
10.1021/jo801803m 2009 American Chemical Society
Published on Web 11/13/2008

Katsuki-Jacobsen Oxidation-Epoxidation
SCHEME 2. Failed Epoxidation-Cyclization Experiments
should be pointed out that acyclic dienyl sulfones were not good
substrates for this chemistry.11a
Despite the fact that terminal olefins have led to selectivities
worse than those with substituted olefins in Katsuki-Jacobsen
epoxidations, we decided to explore the Jacobsen epoxidation
of R-hydroxy dienyl sulfoxides 3a,b,d (Scheme 1) and sulfone
4a, under the conditions reported by Fuchs, hoping that the
combined effects of the allylic stereocenter and the chiral
catalyst would lead to useful stereocontrol. These experiments
resulted in a fast oxidation of sulfur to the corresponding
R-hydroxy dienyl sulfones 4, followed by a slow distal epoxi-
dation. Subsequent treatment of the intermediate monoepoxides
5 and 6 with catalytic CSA afforded the expected sulfonyl
dihydrofurans 8 with a modest increase of 2,5-trans selectivity
(ca. 60:40), thus reversing the selectivity found for the m-CPBA
protocol. In these cases, 2,5-trans-dihydrofurans 8a,b,d were
the major isomers in the final mixtures, with low (Table 1, entry
1) to moderate (Table 1, entry 2) conversions and fair selectivi-
ties. Longer reaction times and sequential additions of reagents
were key for improving the conversion to the final products
(Table 1, entries 3 and 4).
Table 2 gathers the results obtained for substrates ent-4a and
2a with an R configuration at the allylic center. The use of (R,R)-
JC for substrates ent-4a and 2a (Table 2, entries 1 and 2) led
to the same selectivity observed with m-CPBA (favoring 2,5-
cis-dihydrofuran ent-7a after cyclization). On the other hand,
using the enantiomeric catalyst (S,S)-JC (Table 2, entry 3) with
diene 2a led to an enriched mixture of 2,5-trans-dihydrofuran
ent-8a, after cyclization with CSA.
treatment of the chosen diastereomers 3a-d, prepared as
described above, with m-CPBA in toluene resulted in a fast
oxidation of sulfur, producing sulfones 4a-d, followed by a
slow epoxidation at the distal double bond with low stereo-
chemical control. In a one-pot sequence, the resulting monoe-
poxides 5a-d/6a-d were treated with catalytic CSA to afford
good yields of predominantly 2,5-cis mixtures of sulfonyl
dihydrofurans 7a-d/8a-d that were difficult to separate by
chromatography. Silylation of these mixtures with TBSCl in
the presence of imidazole allowed for a straightforward separa-
tion of both diastereomers by column chromatography.
Results and Discussion
With these preliminary results, we decided to modify our
substrates to improve the selectivity of the process. The presence
of bulky groups in the substrates has been shown to be important
for improving the enantioselectivities in these epoxidations.12
Therefore, introducing different silyl ethers on the hydroxyl
group of our substrates seemed to be an interesting and
accessible transformation. This goal was accomplished with
commercially available chlorosilanes, Et3N, and DMAP in DMF,
rendering silyl ethers 11a-g from hydroxy dienyl sulfoxides
3a-c (Scheme 3). It should be pointed out that TIPS and
TBDPS derivatives could not be prepared under a variety of
conditions, including the use of TIPSOTf, leading instead to
recovered starting materials. The unoptimized yields of these
protections ranged from moderate (60-63%) to good (89%),
with the recovery of starting material in some cases. With
substrate 3d (R ) tert-butyl), no reaction was observed, perhaps
due to its considerable steric hindrance. The protection of alcohol
2a with an R configuration in the allylic center afforded silyl
ether 12a and is also shown in scheme 3.
In view of the low selectivities associated with the use of
m-CPBA, we decided to explore other alternatives. The use of
pure anhydrous m-CPBA instead of the commercially available
reagent did not lead to a substantial enhancement of selectivity.
Similarly, the reaction of diene 3a with CF3CO3H7 led just to
sulfonyl diene 4a. Furthermore, the epoxidation of substrate 4a
under Payne conditions occurred with no changes in selectivity
(60:40) and lower yield.8 After these disappointing results, we
chose to explore enantioselective epoxidation conditions with
our R-hydroxy dienyl sulfoxides or derivatives. Unfortunately,
Shi’s epoxidation of sulfonyl diene 4a using commercially
available D-Epoxone resulted in recovered starting material
(Scheme 2).9
Katsuki-Jacobsen epoxidation, using the commercially avail-
able catalysts developed by Jacobsen, (R,R)-JC and (S,S)-JC,10
seemed to be a good option primarily due to the excellent results
obtained by Fuchs for cyclic dienyl sulfones.11 Nonetheless, it
(4) (a) Ferna´ndez de la Pradilla, R.; Montero, C.; Priego, J.; Mart´ınez-Cruz,
L. A. J. Org. Chem. 1998, 63, 9612–9613. (b) Ferna´ndez de la Pradilla, R.;
Manzano, P.; Montero, C.; Priego, J.; Mart´ınez-Ripoll, M.; Mart´ınez-Cruz, L. A.
J. Org. Chem. 2003, 68, 7755–7767.
(5) Available in one step by the procedure of Craig: Craig, D.; Daniels, K.;
MacKenzie, A. R. Tetrahedron 1993, 49, 11263–11304.
(6) (a) Posner, G. H.; Mallamo, J. P.; Miura, K.; Hulce, M. Pure Appl. Chem.
1981, 53, 2307–2314. (b) Cheng, H.-C.; Yang, T.-H. Tetrahedron Lett. 1990,
31, 673–676. (c) Solladie´, G.; Moine, G. J. Am. Chem. Soc. 1984, 106, 6097–
6098. (d) Fawcett, J.; House, S.; Jenkins, P. R.; Lawrence, N. J.; Russell, D. R.
J. Chem. Soc., Perkin Trans. 1 1993, 67–73.
(10) (R,R)-N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminoman-
ganese(III), (R,R)-JC and (S,S)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cy-
clohexanediaminomanganese(III), (S,S)-JC. (a) Jacobsen, E. N.; Zhang, W.; Muci,
A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063–7064. For
epoxidations of dienes and enynes, see refs 3a, 3b.
(11) (a) Hentemann, M. F.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 5615–
5618. (b) Chen, Y.; Evarts, J. B., Jr.; Torres, E.; Fuchs, P. L. Org. Lett. 2002,
4, 3571–3574. (c) Evarts, J.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc. 2002,
124, 11093–11101. (d) Torres, E.; Chen, Y.; Kim, I. C.; Fuchs, P. L. Angew.
Chem., Int. Ed. 2003, 42, 3124–3131. (e) El-Awa, A.; Fuchs, P. Org. Lett. 2006,
8, 2905–2908. (f) Noshi, M. N.; El-Awa, A.; Fuchs, P. L. J. Org. Chem. 2008,
73, 3274–3277.
(12) For a preliminary communication on this chemistry, see: (a) Ferna´ndez
de la Pradilla, R.; Castellanos, A. Tetrahedron Lett. 2007, 48, 6500–6504. For
a leading report on the influence of sterically demanding groups on the Jacobsen
epoxidation, see: (b) Jacobsen, E. N.; Deng, L.; Furukawa, Y.; Mart´ınez, L. E.
Tetrahedron 1994, 50, 4323–4334.
(7) (a) Lee, K.-W.; Choi, H.; Lee, B.-H.; Choi, B.-S.; Chang, J.-H.; Kim,
Y.-K.; Lee, J.-H.; Heo, T.; Nam, D.-H.; Shin, H. Synlett 2005, 3136–3138. (b)
Wiktelius, D.; Berts, W.; Jensen, A. J.; Gullbo, J.; Saitton, S.; Cso¨regh, I.;
Luthman, K. Tetrahedron 2006, 62, 3600–3601.
(8) Payne, G. B. Tetrahedron 1962, 18, 763–765.
(9) (a) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org.
Chem. 1998, 63, 2948–2953. (b) Burke, C. P.; Shi, Y. Angew. Chem., Int. Ed.
2006, 45, 4475–4478.
J. Org. Chem. Vol. 74, No. 1, 2009 171

Ferna´ndez de la Pradilla et al.
TABLE 1. Jacobsen Epoxidation of (S)-Hydroxy Sulfinyl and Sulfonyl Dienes
entry
1
substrate
sulfur oxidation state
conditions
7.5% (R,R)-JC
yieldb
4a (R ) n-Pent)
SO2p-Tola
30% 4a + 25% 8a (64:36)
1.5 equiv of NH4OAc
12.0 equiv of H2O2, 1 day
5% (R,R)-JC
1.0 equiv of NH4OAc
8.0 equiv of H2O2, 16 h
15% (R,R)-JC
3.0 equiv of NH4OAc
24.0 equiv of H2O2, 6 days
20% (R,R)-JC
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 7 days
2
3
4
3a (R ) n-Pent)
3b (R ) i-Pr)
3d (R ) t-Bu)
SOp-Tol
SOp-Tol
SOp-Tol
30% 4a + 60% 8a (60:40)
74% 8b (66:34)
75% 8d (65:35)c
a Sulfone 4a was obtained by oxidation of sulfoxide 3a with 1.5 equiv of MMPP in MeOH (2 h, 78%). b Yields of pure products after column
chromatography. c The 1H NMR spectrum of the mixture of vinyl oxiranes suggested the presence of sulfinyl monoepoxides (ca. 28%), but after
cyclization with CSA, we could not isolate the corresponding sulfinyl dihydrofurans.
TABLE 2. Jacobsen Epoxidation of (R)-Hydroxy Sulfinyl and Sulfonyl Dienes
entry
1
substrate
sulfur oxidation state
conditions
7.5% (R,R)-JC
yieldb
ent-4a (R ) n-Pent)
SO2p-Tola
27% ent-4a + 60% ent-8a/ent-7a (46:54)
1.5 equiv of NH4OAc
12.0 equiv of H2O2, 1 day
25% (R,R)-JC
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 11 days
25% (S,S)-JC
2
3
2a (R ) n-Pent)
2a (R ) n-Pent)
SOp-Tol
SOp-Tol
90% ent-8a/ent-7a (40:60)
88% ent-8a/ent-7a (57:43)
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 11 days
a Sulfone ent-4a was obtained by oxidation of sulfoxide 2a with 1.5 equiv of MMPP in MeOH (2 h, 78%). b Yields of pure products after column
chromatography.
Table 3 summarizes the results for the epoxidation and
cyclization of silyloxy derivatives 11a-g. The crude mixtures
were filtered through silica gel, treated with TBAF in THF to
cleave the silyl ether, and then cyclized in the presence of CSA.
In the early experiments that did not reach completion, silyloxy
sulfonyl dienes 13 were present in the crude mixtures; these
led to sulfonyl dienols 4 upon deprotection. Performing
sequential additions of reagents improved the conversions and
yields of these epoxidations. In spite of the moderate yield
(60%), the use of a TBS group (Table 3, entry 1, substrate 11a)
produced an increase in trans selectivity and, after desilylation
and cyclization, resulted in a 71:29 ratio favoring the 2,5-trans
isomer 8a. This result represents a considerable improvement
relative to the substrate, with the free OH using (R,R)-JC. In
contrast, the treatment of 11a with m-CPBA in toluene led to
an equimolar mixture of diastereomeric vinyl oxiranes. Alter-
natively, the reaction of 11a with (S,S)-JC (mismatched pair)
afforded silyloxy sulfonyl diene 13a and a (40:60) mixture of
monoepoxides 14a that were not desilylated/cyclized (Table 3,
entry 2).
The use of a TES group (Table 3, entries 3 and 4, substrate
11b) produced a slight increase in selectivity (77:23) with (R,R)-
JC and gave a result identical to entry 2 with (S,S)-JC (Table
3, entry 4). Similarly, the use of an i-Bu3Si group (Table 3,
172 J. Org. Chem. Vol. 74, No. 1, 2009

Katsuki-Jacobsen Oxidation-Epoxidation
SCHEME 3. Silylation of r-Hydroxy Sulfinyl Dienes
position of the diene system. Both are important moieties present
in a wide range of natural products such as the Annonaceous
acetogenins13 or the amphidinolides.14 Following the same
methodology described before for nonsubstituted dienes, R-hy-
droxy dienyl sulfoxides 15a,b and 16a,b were prepared in good
yields from the corresponding sulfinyl dienes (Scheme 4). These
diastereomers could be interconverted readily by a Mitsunobu
protocol. Prior to submitting our new R-hydroxy sulfinyl dienes
to the Jacobsen epoxidation and cyclization, we tested the
behavior of substrates 16a,b with the m-CPBA/CSA protocol.
Thus, hydroxy sulfinyl diene 16a afforded an inseparable
mixture of the two possible sulfonyl dihydrofurans 20 and 21
with low selectivity, with the 2,5-cis being the major diastere-
omer (Scheme 4). When substrate 16b was treated with
m-CPBA/CSA, the major sulfonyl dihydrofuran in the mixture
was 23. Thus, a slight reversal of the general trend was observed
when a methyl substituent is located in the internal position of
the diene.
In view of the good selectivities obtained before with the
Bu3Si group, we decided to use it again as a reference
protecting-directing group for the new substrates. Scheme 5
summarizes the silylation and oxidation of these more substi-
tuted dienes to which afford the expected silyloxy derivatives
(24a,b, 25, 26a,b, and ent-26a). It should be mentioned that
sulfinyl dienol 15b could not be protected in this manner, leading
instead to the complete recovery of starting material.
entry 5) led to a 90:10 ratio of dihydrofurans with (R,R)-JC,
and the epoxidation with the enantiomeric catalyst (Table 3,
entry 6) resulted in lower reactivity and selectivity (mismatched
pair). With Bu3Si derivative 11d and (R,R)-JC, a 90:10
selectivity was observed (Table 3, entry 7) with excellent yield.
To clarify the role of the sulfoxide in the process, this protocol
was applied to sulfone 13d (Table 3, entry 8), with comparable
results. Thus, it appears that the sulfoxide moiety does not exert
a significant influence on the stereochemical outcome of the
process. Then we decided to check the effect of a Hex3Si group,
and the selectivity found was 90:10 again (Table 3, entry 9).
Finally, the scope of the methodology was tested with substrates
11f (R ) isopropyl) and 11g (R ) Ph) (Table 3, entries 10 and
11), which bear a Bu3Si protecting group. In both cases, the
selectivity measured was 90:10.
These results suggested that bulky and ramified silyl ethers
at the allylic position were effective directing groups, increasing
the anti selectivity in the epoxidation due to their steric
hindrance that blocks a face of the diene. The enhanced
selectivity found for silyl ethers bearing longer alkyl chains is
noteworthy (Table 3, compare entries 3 and 7).
Table 4 shows the experiments carried out with substrate 12a
with an R configuration at the allylic position. The use of (R,R)-
JC gave a 60:40 selectivity favoring epoxidation by the face
that produces 2,5-trans-dihydrofurans after cyclization. With
(S,S)-JC, the trans selectivity increased to 86:14. In both cases,
the yields of the final product ent-8a were good after four
additions of reagents in the oxidation-epoxidation step. Thus,
it appears that the stereochemical outcome of the process is
primarily controlled by the substrate. The optical purity of
dihydrofurans 8a and ent-8a was secured by formation of their
TBDMS ethers and by separation and comparison of their optical
rotation data with data measured for samples obtained with
m-CPBA.
Table 5 shows the results of the epoxidation under Jacobsen’s
conditions for substrates 16a, 24a, 26a, 15a, 25, and ent-26a.
During these experiments, we were able to isolate and partially
characterize the mixtures of monoepoxides 19/27, 28/29, ent-
19a/ent-27, and ent-28/ent-29 prior to their cyclization into the
corresponding dihydrofurans. As it was mentioned before for
simpler substrates, the reactions were generally slow and
required sequential additions of reagents over a few days to
reach completion, with a fast oxidation of the sulfinyl group to
the sulfone being observed. The initial experiments were carried
out with 16a and 15a having a free hydroxyl group; these
substrates afforded selectivities better for the matched pairs
(Table 5, entries 1 and 3) than when the diene was not
substituted, in agreement with the general rule that substituted
olefins are better substrates for Jacobsen’s epoxidation. Epoxi-
dation with (R,R)-JC afforded an 87:13 mixture of monoep-
oxides 19a/27 when starting from hydroxy sulfinyl diene 16a
(Table 5, entry 1). Subsequent cyclization with CSA gave a
mixture of sulfonyl dihydrofurans 21 and 30. Separation of this
mixture by column chromatography allowed us to identify (by
NMR and NOE analysis) each diastereomer and to conclude
that both products had 2,5-trans configuration and were epimers
at the new stereocenter C-2′. The major product 21 was identical
to the minor product obtained with the m-CPBA/CSA protocol.
The minor product 30 should arise from a cis-monoepoxide 27
by acid-catalyzed cyclization. Reaction of 16a with (S,S)-JC
(Table 5, entry 2) resulted in an incomplete epoxidation after
four additions of reagents and 5 days (mismatched pair).
Cyclization mediated by CSA gave a 75:25 mixture of sulfonyl
dihydrofurans 20/21 analogous to that obtained with m-CPBA/
CSA. It is noteworthy that with hydroxy sulfinyl diene 15a
reasonable catalyst-directed diastereoselectivities were achieved
Encouraged by these promising results, we decided to extend
the study of this epoxidation-cyclization protocol to more
substituted dienes, with the purpose of obtaining more substi-
tuted tetrahydrofurans in high diastereomeric ratios. This
approach would allow us to access dihydrofurans with an
additional stereocenter when starting from a diene with a
substituent in the terminal position and dihydrofurans with a
quaternary center when a substituent is placed in the internal
(13) Bermejo, A.; Figade`re, B.; Zafra-Polo, M. C.; Barrachina, I.; Estornell,
E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303.
(14) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.; Kawabata, J.;
Katsumata, K.; Horiguchi, T.; Kobayashi, J. J. Org. Chem. 2003, 68, 5339–
5345.
J. Org. Chem. Vol. 74, No. 1, 2009 173

Ferna´ndez de la Pradilla et al.
TABLE 3. Jacobsen Epoxidation of (S)-Silyloxy Sulfinyl and Sulfonyl Dienes
entry
1
substrate
P
sulfur oxidation state
conditions
5% (R,R)-JC
yielda
11a (R ) n-Pent)
TBS
SOp-Tol
30% 4a + 60% 8a (71:29)
1.0 equiv of NH4OAc
8.0 equiv of H2O2, 2 days
5% (S,S)-JC
1.0 equiv of NH4OAc
8.0 equiv of H2O2, 2 days
5% (R,R)-JC
1.0 equiv of NH4OAc
8.0 equiv of H2O2, 2 days
5% (S,S)-JC
1.0 equiv of NH4OAc
8.0 equiv of H2O2, 3 days
10% (R,R)-JC
2.0 equiv of NH4OAc
16.0 equiv of H2O2, 3 days
20% (S,S)-JC
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 6 days
20% (R,R)-JC
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 6 days
15% (R,R)-JC
3.0 equiv of NH4OAc
24.0 equiv of H2O2, 6 days
25% (R,R)-JC
2
11a (R ) n-Pent)
11b (R ) n-Pent)
11b (R ) n-Pent)
11c (R ) n-Pent)
11c (R ) n-Pent)
11d (R ) n-Pent)
13d (R ) n-Pent)
11e (R ) n-Pent)
11f (R ) i-Pr)
TBS
SOp-Tol
SOp-Tol
SOp-Tol
SOp-Tol
SOp-Tol
SOp-Tol
SO2p-Tolc
SOp-Tol
SOp-Tol
SOp-Tol
13a (49) + 14a (51) (40:60)b
35% 4a + 60% 8a (77:23)
13c (51) + 14c (49) (40:60)b
24% 4a + 73% 8a (90:10)
21% 4a + 75% 8a (64:36)
89% 8a (90:10)
3
TES
4
TES
5
i-Bu3Si
i-Bu3Si
Bu3Si
Bu3Si
Hex3Si
Bu3Si
Bu3Si
6
7
8
97% 14a (90:10)b
9
90% 8a (90:10)
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 6 days
15% (R,R)-JC
3.0 equiv of NH4OAc
24.0 equiv of H2O2, 6 days
20% (R,R)-JC
10
11
95% 8b (90:10)
11g (R ) Ph)
95% 8c (90:10)
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 5 days
a Yields of pure products after column chromatography. b Mixtures that were not desilylated/cyclized. Data taken from 1H NMR of the crude
products. c Sulfone 13d was obtained from sulfoxide 11d by oxidation with 1.5 equiv of MMPP in MeOH (2 h, 71%).
in favor of the major products 2,5-trans-dihydrofuran ent-21
and 2,5-cis-dihydrofuran ent-20, respectively (Table 5, entries
3 and 4).
selectivity (96:4) (Table 5, entry 7). After desilylation and
cyclization of the 96:4 mixture of monoepoxides ent-28/ent-
29, only the major sulfonyl dihydrofuran ent-21 was isolated.
In a matched scenario, sulfonyl derivatives 26a and ent-26a
(Table 5, entries 8 and 10) produced a slight, but appreciable,
drop in the formation of the minor products to almost the
limit of detection (99:1 ratio) for the reaction of ent-26a with
(S,S)-JC (Table 5, entry 10). We do not have a clear
explanation for this small enhancement of selectivity found
for the dienyl sulfones relative to the related sulfoxides.
Finally, the epoxidation of sulfone 26a with (S,S)-JC (Table
5, entry 9) led to a 76:24 mixture of monoepoxides 28 and
28′, which was not cyclized.
The Jacobsen epoxidation of silylated substrates (P )
SiBu3) led again to an important increase in the selectivity
of the process. With these derivatives, it was necessary to
desilylate (TBAF in THF) the mixtures of monoepoxides
prior to cyclization. Although we observed variable amounts
of dihydrofurans after the reaction with TBAF, we decided
to maintain the treatment with CSA to ensure that cyclization
was complete. The reaction of silyloxy sulfinyl diene 24a
with (R,R)-JC gave a highly selective mixture of monoep-
oxides 28 and 29 (96:4), which was transformed into
dihydrofurans 21 and 30 in good yields after three steps
(Table 5, entry 5). The mismatched pair (reaction with (S,S)-
JC) for substrate 24a afforded a mixture of dihydrofurans
20/21 comparable to that obtained with m-CPBA/CSA (Table
5, entry 6). On the other hand, the reaction of silyloxy
derivative 25 with (S,S)-JC also showed an excellent
To test the usefulness of this process for obtaining densely
functionalized tetrahydrofuran derivatives, we examined the
nucleophilic epoxidation of 21, which afforded a 93:7 mixture
of sulfonyl oxiranes 31 in good yield (Scheme 6).4 Our
recently described reductive cleavage of this moiety with
174 J. Org. Chem. Vol. 74, No. 1, 2009

Katsuki-Jacobsen Oxidation-Epoxidation
TABLE 4. Jacobsen Epoxidation of (R)-Silyloxy Sulfinyl and
with low selectivity, affording after cyclization a 39:61 mixture
of sulfonyl dihydrofurans 22 and 23 (Table 6, entry 1). To our
surprise, silyloxy derivative 24b led to mixtures of sulfinyl
oxiranes 33 (Table 6, entries 2 and 3). Considering that the
reaction conditions were comparable to other cases studied, it
is a peculiar behavior that is probably related to the conformation
adopted by this diene. It is tentatively proposed that the methyl
group in this position is forcing a certain arrangement of the
allylic center so that the oxidant can not access readily the sulfur
atom lone pair because of the presence of the bulky silyl ether.
As expected, a reversal in the facial selectivity was achieved
by changing to the enantiomeric catalyst. Due to the low
selectivities found, these mixtures of monoepoxides were not
studied any further. Finally, sulfonyl silyloxy derivative 26b
afforded a modest increase in selectivity to 23:77 (Table 6, entry
4).
Sulfonyl Dienes
entry substrate sulfur oxidation state conditions
yielda
1
12a
SOp-Tol
20% (R,R)-JC 98% ent-8a (60:40)
4.0 equiv of
NH4OAc
32.0 equiv of
H2O2, 11 days
We have rationalized the results of this study on the basis of
a conformational analysis of the starting material, assuming an
early transition state with the more stable conformer that is also
the more reactive. We have also taken into account that the
sulfoxide does not participate in the process because it is rapidly
oxidized to the sulfone under these reaction conditions in most
cases we examined. The precise balance of allylic 1,2-strain (R
and the sulfonyl moiety) and 1,3-strain (R and the remote double
bond) would dictate that the favored reactive conformer is A in
all cases tested.
2
12a
SOp-Tol
20% (S,S)-JC 89% 8a (86:14)
4.0 equiv of
NH4OAc
32.0 equiv of
H2O2, 11 days
a Yields of pure products after column chromatography.
SCHEME 4. Substrates with Substitution in the Diene
System
Unsubstituted Dienes. For substrates with an S configuration
at the allylic center, the predominant approach of the oxo
complex occurs by the ꢀ face of the molecule, affording an
anti-monoepoxide (Scheme 7). This intermediate is the precursor
of 2,5-trans-sulfonyl dihydrofurans. When P is a bulky silyl
ether (such as Bu3Si), its presence dictates the facial selectivity
of the epoxidation, and it is responsible for the increased
selectivities. Similarly, for substrates with an R configuration
at the allylic center, the approach of the oxo complex by the R
face of the diene on the major conformer A produces an anti-
monoepoxide as the major product.
Substituted Dienes. Once the absolute stereochemistry of
the sulfonyl dihydrofurans isolated was determined by careful
analysis of their NMR data, including NOE experiments, and
by relying on the known stereochemical outcome of the results
found for m-CPBA, we hypothesized that the minor 2,5-trans
products should arise from a cis-monoepoxide. In the case of
(S)-hydroxy and -silyloxy sulfonyl dienes, an R attack of the
oxo complex to the reactive conformer A, followed by evolution
of the radical intermediate, leading to the cis-monoepoxide is
proposed (Scheme 8). For the R series, a ꢀ attack of the oxo
complex to the reactive conformer and subsequent evolution
of the radical intermediate are supposed to be the key to the
formation of a cis-monoepoxide that results in the minor sulfonyl
dihydrofuran. The loss of geometry in Jacobsen epoxidations
has been previously observed and generally gives rise to trans-
oxiranes from cis-alkenes. In our case, it is noteworthy that we
obtain trans-monoepoxides as major products in the epoxidation
of trans-olefins and just small amounts of cis-oxiranes that are
almost suppressed when P is a bulky silyl group. The precise
origin of these observations is uncertain.
15
freshly prepared MgI2 gave cleanly the desired ketone 32,
thus opening a wide range of future synthetic applications.
Table 6 summarizes the results obtained for hydroxy and
silyloxy sulfinyl dienes with internal substitution at the diene
moiety, which unfortunately did not lead to useful levels of
diastereoselectivity. The reaction of 16b with (R,R)-JC occurred
Synthetic Applications. Substituted tetrahydrofurans are
commonly occurring substructures found in a broad array of
natural products and biologically active molecules such as
Laurencia sesquiterpenes ((s)-kumausallene), polyether anti-
biotics (pamamycin-607), and Annonaceous acetogenins (mu-
(15) Ferna´ndez de la Pradilla, R.; Alhambra, C.; Castellanos, A.; Ferna´ndez,
J.; Manzano, P.; Montero, C.; Uren˜a, M.; Viso, A. J. Org. Chem. 2005, 70,
10693–10700.
J. Org. Chem. Vol. 74, No. 1, 2009 175

Ferna´ndez de la Pradilla et al.
TABLE 5. Epoxidation-Cyclization Reactions of Substrates with Terminal Substitution
entry
1
substrate
conditions
25% (R,R)-JC
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 6 days
20% (S,S)-JC
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 5 days
25% (S,S)-JC
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 10 days
25% (R,R)-JC
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 10 days
15% (R,R)-JC
3.0 equiv of NH4OAc
24.0 equiv of H2O2, 4 days
20% (S,S)-JC
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 9 days
20% (S,S)-JC
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 7 days
20% (R,R)-JC
monoepoxides
dihydrofuransc
yieldd
70%
19a (87)/27 (13)a c
21 (87)/30 (13)
20 (75)/21 (25)
ent-21 (83)/ent-30 (17)
ent-20 (84)/ent-21 (16)
21 (96)/30 (4)
,
16a
b
2
16a
15a
15a
24a
24a
25
64%
71%
55%
77%
57%
69%
81%
ent-19a (83)/ent-27 (17)a c
,
3
b
4
28 (96)/29 (4)a c
,
5
b
6
20 (73)/21 (27)
ent-21
ent-28 (96)/ent-29 (4)a c
,
7
28 (97)/29 (3)a c
,
8
26a
26a
ent-26a
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 5 days
25% (S,S)-JC
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 11 days
30% (S,S)-JC
9
28 (76)/28′ (24)a, c
ent-28 (99)/ent-29 (1)a c
ent-21
51%
,
10
6.0 equiv of NH4OAc
48.0 equiv of H2O2, 7 days
a Mixtures of monoepoxides isolated by filtration through silica gel. b Mixtures of monoepoxides that were directly desilylated/cyclized. c Data taken
from H NMR of the crude products. d Combined yields (two or three steps) of pure products after column chromatography.
1
ricatetrocin C).16 Due to the importance of these molecules and
their interesting activity and unique structural characteristics,
considerable effort has been devoted toward the development
of methods for the stereoselective construction of substituted
tetrahydrofurans.17
As an application of this study and in connection with our
interest in the synthesis of natural products containing substituted
THF rings, we report here the formal syntheses of the marine
epoxy lipids (6S,7S,9R,10R)-6,9-epoxynonadec-18-ene-7,10-diol
3518 and (6S,7S,9S,10S)-6,9-epoxynonadec-18-ene-7,10-diol
36.19 Since their isolation and because of their peculiar
substitution, these natural products have been studied in-depth,
and they have been the target of several synthetic efforts.20 Our
synthetic plan is shown in Scheme 9. We envisioned that we
could access both natural products starting from the same
R-hydroxy sulfinyl diene 3a because the stereocenter at C-6
would be determined by the allylic center in 3a or 11d, and we
could introduce the correct stereochemistry at C-9 by choosing
(16) (a) Suzuki, T.; Koizumi, K.; Suzuki, H.; Kurosawa, E. Chem. Lett. 1983,
1639–1642. (b) Faul, M.; Huff, B. E. Chem. ReV. 2000, 100, 2407–2474. (c)
Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540.
(17) For reviews, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309–
3362. (b) Harmange, J.-C.; Figade`re, B. Tetrahedron: Asymmetry 1993, 4, 1711–
1754. (c) Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301–2323. (d)
Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290.
(18) Warren, R. G.; Wells, R. J.; Blount, J. F. Aust. J. Chem. 1980, 33, 891–
898.
(19) Capon, R. J.; Barrow, R. A.; Rochfort, S.; Jobling, M.; Skene, C.
Tetrahedron 1998, 54, 2227–2242.
176 J. Org. Chem. Vol. 74, No. 1, 2009

Katsuki-Jacobsen Oxidation-Epoxidation
SCHEME 5. Silylation and Oxidation of Substituted
Sulfinyl Dienols
SCHEME 7. Stereochemical Outcome of the Process for
Unsubstituted Dienes
SCHEME 6. Synthesis of Tetrahydrofuran 32
as a benzoate 41, then the silyl ether on the primary alcohol
was cleaved with Dowex in good yield for the two steps,
affording 42. Swern oxidation afforded the desired aldehyde
43 that had been transformed into 35 in one step by addition of
the appropriate Grignard reagent. The spectroscopic data of 43
were identical to the reported values.20a
Our synthetic approach to natural product 36 begins with the
epoxidation/cyclization of hydroxy sulfinyl diene 3a with
m-CPBA/CSA to give a 60:40 inseparable mixture of sulfonyl
dihydrofurans 8a (Scheme 11). The silylation and separation
of the mixture allowed us to access 2,5-cis-dihydrofuran 9a that
underwent a nucleophilic epoxidation to afford sulfonyl oxirane
44 as single isomer. The treatment of 44 with MgI2 gave
mixtures of the desired ketone 46 and a dimeric product 51 in
the type of epoxidation. Jacobsen’s epoxidation, as described
in this article for 11d (P ) SiBu3), would lead to a 2,5-trans-
sulfonyl dihydrofuran that could be converted into the natural
product 35. Using the m-CPBA/CSA protocol on 3a (P ) H)
would afford predominantly, but with low selectivity, the 2,5-
cis-dihydrofuran that could be transformed into the natural
product 36 in a few steps.
As described before, Jacobsen epoxidation of silyloxy sulfinyl
diene 11d gave a 90:10 mixture of monoepoxides 14d that, after
deprotection/cyclization, afforded an inseparable mixture of
sulfonyl dihydrofurans 8a (Scheme 10). Protection of the
primary alcohol as a tert-butyldimethylsilyl ether in excellent
yield allowed for the separation of diastereomers by chroma-
tography as well as for the subsequent differentiation of the
primary and secondary hydroxyls. Nucleophilic epoxidation of
2,5-trans diastereomer 10a with KOOt-Bu gave sulfonyl oxirane
37 as a single isomer in excellent yield.21 The reductive cleavage
of sulfonyl oxiranes developed by our group with freshly
prepared MgI2, followed by reduction of ketone 38 with
L-Selectride, afforded an 85:15 mixture of alcohols 39/40. After
chromatographic separation, the secondary alcohol was protected
(20) For the synthesis of 35, see: (a) Williams, D. R.; Harigaya, Y.; Moore,
J. L.; D’sa, A. J. Am. Chem. Soc. 1984, 106, 2641–2644. (b) Hatakeyama, S.;
Sakurai, K.; Saijo, K.; Takano, S. Tetrahedron Lett. 1985, 26, 1333–1336. (c)
Gurjar, M. K.; Mainkar, P. S. Heterocycles 1990, 31, 407–410. (d) Chikashita,
H.; Nakamura, Y.; Uemura, H.; Itoh, K. Chem. Lett. 1993, 477–480. (e) Capon,
R. J.; Barrow, R. A.; Skene, C.; Rochfort, S. Tetrahedron Lett. 1997, 38, 7609–
7612. (f) Wang, Z.-M.; Shen, M. J. Org. Chem. 1998, 63, 1414–1418. (g) Mori,
Y.; Sawada, T.; Furukawa, H. Tetrahedron Lett. 1999, 40, 731–734. (h) Garc´ıa,
C.; Soler, M. A.; Mart´ın, V. S. Tetrahedron Lett. 2000, 41, 4127–4130. (i) Garc´ıa,
C.; Mart´ın, T.; Mart´ın, V. S. J. Org. Chem. 2001, 66, 1420–1428. For the
synthesis of 36, see refs 20e, h, i. (j) Yoda, H.; Muruyama, K.; Takabe, K.
Tetrahedron: Asymmetry 2001, 12, 1403–1406. (k) Gadikota, R. R.; Callam,
C.; Lowary, T. L. J. Org. Chem. 2001, 66, 9046–9051.
(21) Sulfonyl oxiranes are versatile synthetic intermediates. For leading
references, see: (a) Mori, Y.; Takase, T.; Noyori, R. Tetrahedron Lett. 2003,
44, 2319–2322. (b) Inoue, M.; Yamashita, S.; Tatami, A.; Miyazaki, K.; Hirama,
M. J. Org. Chem. 2004, 69, 2797–2804. (c) Furuta, H.; Hase, M.; Noyori, R.;
Mori, Y. Org. Lett. 2005, 7, 4061–4064. (d) D´ıez, D.; Templo Bene´itez, M.;
Gil, M. J.; Moro, R. F.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Urones, J. G.
Synthesis 2005, 565–568.
J. Org. Chem. Vol. 74, No. 1, 2009 177

Ferna´ndez de la Pradilla et al.
TABLE 6. Epoxidation-Cyclization Reactions of Substrates with Internal Substitution
entry
1
substrate
conditions
20% (R,R)-JC
monoepoxidesa
dihydrofuransc
22 (39)/23 (61)
yieldd
78%
16b
4.0 equiv of NH4OAc
32.0 equiv of H2O2, 6 days
25% (R,R)-JC
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 5 days
30% (S,S)-JC
6.0 equiv of NH4OAc
48.0 equiv of H2O2, 7 days
25% (R,R)-JC
33 (69:31)b c
75%
57%
53%
,
2
3
4
24b
24b
26b
33 (44:56)b c
,
34 (23:77)c
22 (23)/23 (77)
5.0 equiv of NH4OAc
40.0 equiv of H2O2, 6 days
a Isolated mixtures of monoepoxides after filtration by column chromatography. b Mixtures of monoepoxides that were not desilylated/cyclized. c Data
taken from H NMR of the crude products. d Combined yields (two or three steps) of pure products after column chromatography.
1
SCHEME 8. Stereochemical Outcome of the Process for Substituted Dienes
variable ratios (see Supporting Information). It should be pointed
out that 51 was obtained as a single isomer that was tentatively
assigned as shown in Scheme 11. In view of these unexpected
results, we examined the cleavage with MgBr2,22 which led
smoothly to R-bromoketone 45 that was dehalogenated with
Al-Hg,23 producing cleanly the desired ketone 46. Reduction
of the carbonyl group with NaBH4 gave an 83:17 mixture of
alcohols. After separation by chromatography, secondary alcohol
47 was protected as a benzoate 49, and the silyl ether was
cleaved with Dowex to give the desired alcohol 50 in good yield
178 J. Org. Chem. Vol. 74, No. 1, 2009

Katsuki-Jacobsen Oxidation-Epoxidation
SCHEME 9. Synthetic Plan for the Synthesis of Epoxy
Lipids 35 and 36
SCHEME 11. Formal Synthesis of 36
SCHEME 10. Formal Synthesis of 35
ultimately lead to densely functionalized tetrahydrofurans. In
addition, these methodologies have been applied to the formal
syntheses of two marine natural products.
Experimental Section
Jacobsen Epoxidation of Tributylsilyloxy Sulfinyl Diene 11d:
From a cold solution (0 °C) of silyloxy sulfinyl diene 11d (60 mg,
0.122 mmol) in a 1:1 mixture of CH2Cl2/MeOH (1.1 mL), NH4OAc
(9.4 mg, 0.122 mmol, 1.0 equiv), (R,R)-JC (4.0 mg, 0.006 mmol,
0.05 equiv), and H2O2 (0.11 mL), according to the general procedure
described in the Supporting Information (for 6 days), and after three
additional loads of reagents, a 90:10 mixture of monoepoxides 14d
(63 mg, 98%) was obtained. Data for 14d: Rf 0.23 (10%
EtOAc-hexane); 1H NMR (300 MHz) δ 0.36 (m, 6 H), 0.84 (t, 12
H, J ) 6.8 Hz), 1.06-1.66 (m, 20 H), 2.42 (s, 3 H), 2.73 (dd, 1 H,
J ) 5.6, 2.4 Hz), 3.04 (dd, 1 H, J ) 5.6, 4.3 Hz), 4.19 (ddd, 1 H,
J ) 9.0, 4.2, 2.4 Hz), 4.50 (dd, 1 H, J ) 8.6, 2.7 Hz), 6.29 (d, 1
H, J ) 9.0 Hz), 6.34 (d, 1 H, J ) 8.8 Hz), 7.31 (d, 2 H, J ) 8.5
Hz), 7.71 (d, 2 H, J ) 8.1 Hz); 13C NMR (75 MHz) δ 13.2 (3 C),
13.8 (3 C), 14.0, 21.6, 22.4, 25.3 (3 C), 25.31, 26.5 (3 C), 31.3,
38.5, 47.9, 48.6, 69.5, 128.5 (2 C), 129.9 (2 C), 136.4, 140.3, 144.6,
150.1; IR (film) 2957, 2925, 2872, 2855, 1465, 1378, 1322, 1299,
1149, 1088, 962, 886, 835, 669 cm-1; MS (ES) 545 [M + Na]+
(100%), 523 [M + H]+. Anal. Calcd for C29H50O4SSi: C, 66.62;
H, 9.64; S, 6.13. Found: C, 66.85; H, 9.37; S, 6.40.
Jacobsen Epoxidation of Hydroxy Sulfinyl Diene 16a: From a
cold solution (0 °C) of hydroxy sulfinyl diene 16a (20 mg, 0.08
mmol) in a 1:1 mixture of CH2Cl2/MeOH (0.72 mL), NH4OAc (6
mg, 0.08 mmol, 1.0 equiv), (R,R)-JC (2.5 mg, 0.004 mmol, 0.05
equiv), and H2O2 (68 µL), according to the general procedure
described in the Supporting Information (for 6 days), and after four
additional loads of reagents, an 87:13 inseparable mixture of
monoepoxides 19a and 27 (20 mg, 88%) was obtained as a colorless
oil.Partialdataforthemixture19a/27:Rf 0.26(50%EtOAc-hexane);
1H NMR (300 MHz) δ 0.87 (t, 3 H, J ) 7.3 Hz), 1.37 (d, 3 H, J
) 5.1 Hz), 1.59 (br s, 1 H), 1.71-1.81 (m, 2 H), 2.42 (s, 3 H),
3.04 (qd, 1 H, J ) 5.1, 2.0 Hz), 3.61 (dd, 1 H, J ) 8.3, 2.0 Hz),
4.50 (dt, 1 H, J ) 9.4, 4.9 Hz), 6.45 (d, 1 H, J ) 8.5 Hz), 6.55 (d,
1 H, J ) 7.5 Hz, min), 7.31 (d, 2 H, J ) 8.1 Hz), 7.72 (d, 2 H, J
for the three steps. Alcohol 50 had been transformed into the
natural product in four steps by the group of Lowary in 2001.20k
Our synthetic 50 showed data identical to that described in the
literature.
Conclusions
The Katsuki-Jacobsen oxidation-epoxidation of R-silyloxy
dienyl sulfoxides unsubstituted at the terminal position, followed
by intramolecular cyclization, leads to 2,5-trans-substituted
sulfonyl dihydrofurans with good selectivity. This methodology
has been successfully extended to more substituted dienes that
(22) (a) Ashwell, M.; Clegg, W.; Jackson, R. F. W. J. Chem. Soc., Perkin
Trans. 1 1991, 897–908. (b) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron
Lett. 1996, 37, 2605–2608. See also ref 21c.
(23) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86, 1639–1640.
J. Org. Chem. Vol. 74, No. 1, 2009 179

Ferna´ndez de la Pradilla et al.
) 8.3 Hz); 13C NMR (75 MHz) δ 10.5, 17.3, 21.6, 30.4, 54.3,
56.8, 70.5, 128.2 (2 C), 129.9 (2 C), 136.6, 140.1, 144.7, 148.2.
Cyclization with CSA of the Mixture of Monoepoxides 19a/27.
Synthesis of (2R,2′R,5S)-1-[5-Ethyl-4-(p-tolylsulfonyl)-2,5-dihydro-
furan-2-yl]ethanol, 30, and (+)-(2R,2′R,5R)-1-[5-Ethyl-4-(p-tolyl-
sulfonyl)-2,5-dihydrofuran-2-yl]ethanol, 21: From a solution of
monoepoxides 19a/27 (20 mg, 0.07 mmol) at rt in CH2Cl2 (0.5
mL) and CSA (7 mg, 0.03 mmol, 0.4 equiv), according to the
general procedure described in the Supporting Information (12 h),
and after purification by column chromatography (20-50%
EtOAc-hexane), minor isomer 30 (3 mg, 13%) and major isomer
21 (19 mg, 84%) were obtained as colorless oils. Partial data for
30: Rf 0.28 (50% EtOAc-hexane); 1H NMR (300 MHz) δ 0.72 (t,
3 H, J ) 7.3 Hz), 1.31 (d, 3 H, J ) 6.2 Hz), 1.84 (m, 2 H), 2.45
(s, 3 H), 3.21 (qd, 1 H, J ) 8.3, 6.2 Hz), 3.96 (m, 1 H), 4.34 (tdd,
1 H, J ) 6.6, 3.3, 2.0 Hz), 6.93 (t, 1 H, J ) 1.6 Hz), 7.33 (d, 2 H,
J ) 8.1 Hz), 7.74 (d, 2 H, J ) 8.4 Hz); NOE H-3/H-2 (2.8%),
H-5/H-2′ (4.0%), H-2/H-3 (3.1%), H-2/CH2 Et (1.7%), H-2/CH3
(3.0%), H-2′/H-5 (4.0%), H-2′/H-2 (0.7%), H-2′/CH3 (4.0%); 13C
NMR (75 MHz) δ 8.3, 17.9, 21.6, 26.1, 69.7, 73.9, 74.6, 128.0 (2
the inseparable mixture 31 (52 mg, 87%) as a colorless oil. Data
for 31a and 31b (from the mixture): Rf 0.30 (10% EtOAc-hexane);
1
[R]20 -23.9 (c ) 5.0); H NMR (300 MHz) δ 0.83 (t, 3 H, J )
D
7.6 Hz), 1.00 (t, 3 H, J ) 7.3 Hz, min), 1.23 (d, 3 H, J ) 6.1 Hz),
1.24 (d, 3 H, J ) 6.3 Hz, min), 1.34-1.43 (m, 2 H), 2.20 (br s, 1
H), 2.44 (s, 3 H), 3.80-3.87 (m, 2 H), 4.05 (s, 1 H), 4.16 (s, 1 H,
min), 4.46 (dd, 1 H, J ) 6.8, 4.7 Hz), 7.36 (d, 2 H, J ) 8.3 Hz),
7.80 (d, 2 H, J ) 8.3 Hz); 13C NMR (75 MHz) δ 9.9, 10.2 (min),
19.7, 21.7, 23.3, 24.0 (min), 61.7 (min), 64.7, 66.5 (min), 67.8, 76.2,
77.9, 78.7 (min), 78.9 (min), 80.3, 128.9 (2 C, min), 129.1 (2 C),
129.9 (2 C), 130.0 (2 C, min), 133.6, 146.0; IR (film) 3514, 2972,
2928, 2878, 1596, 1453, 1379, 1328, 1304, 1149, 1087, 1065, 1018,
903, 813 cm-1; MS (ES) 647 [2M + Na]+, 335 [M + Na]+ (100%),
313 [M + H]+. Anal. Calcd for C15H20O5S: C, 57.67; H, 6.45; S,
10.26. Found: C, 57.47; H, 6.66; S, 9.95.
Reductive Cleavage of Sulfonyl Oxirane 31 with MgI2. Synthe-
sis of (-)-(2S,5R,5′S)-2-Ethyl-5-(1-hydroxyethyl)dihydrofuran-3-
one, 32: From the mixture of oxiranes 31a and 31b (42 mg, 0.13
mmol) in Et2O (0.7 mL) and MgI2 (4.6 mL from a ca. 0.2 M
solution in Et2O, 0.94 mmol, 7.0 equiv), according to the general
procedure described in the Supporting Information (for 4 h), and
after chromatography (20-50% EtOAc-hexane), ketone 32 (20
C), 129.9 (2 C), 136.9, 141.3, 143.2, 144.6. Data for 21: Rf 0.20
1
(50% EtOAc-hexane); [R]20 +96.5 (c ) 5.70); H NMR (500
D
MHz) δ 0.84 (t, 3 H, J ) 7.3 Hz), 1.16 (d, 3 H, J ) 6.6 Hz), 1.61
(ddq, 1 H, J ) 14.4, 7.3, 5.8 Hz), 1.81 (ddq, 1 H, J ) 14.8, 7.3,
3.4 Hz), 1.87 (d, 1 H, J ) 4.6 Hz), 2.43 (s, 3 H), 3.86 (dqd, 1 H,
J ) 8.5, 6.5, 4.4 Hz), 4.80 (ddd, 1 H, J ) 5.6, 3.8, 1.5 Hz), 4.85
(ddd, 1 H, J ) 5.9, 3.4, 1.7 Hz), 6.74 (t, 1 H, J ) 1.5 Hz), 7.33 (d,
2 H, J ) 8.1 Hz), 7.76 (d, 2 H, J ) 8.3 Hz); NOE H-3/H-2 (3.3%),
H-3/CH3 (2.7%), H-2/H-2′ (3.5%), H-2/CH2 Et (1.7%), H-2/CH3
(2.9%), H-2′/H-2 (3.7%), H-2′/CH3 (4.7%); 13C NMR (75 MHz) δ
8.3, 18.0, 21.7, 27.6, 69.1, 85.6, 89.0, 127.9 (2 C), 130.0 (2 C),
136.4, 138.3, 145.0, 145.2; IR (film) 3468, 3084, 2966, 2926, 2872,
1318, 1301, 1289, 1158, 1092, 1065, 815, 667 cm-1; MS (ES) 615
[2M + Na]+, 319 [M + Na]+ (100%).
mg, 94%) was obtained. Data for 32: Rf 0.25 (10% EtOAc-hexane);
1
[R]20 -18.7 (c ) 1.1); H NMR (300 MHz) δ 0.96 (t, 3 H, J )
D
7.3 Hz), 1.12 (d, 3 H, J ) 6.6 Hz), 1.54-1.69 (m, 2 H), 2.02 (br
s, 1 H), 2.34 (dd, 1 H, J ) 18.2, 7.0 Hz), 2.60 (dd, 1 H, J ) 18.2,
8.2 Hz), 3.96 (dd, 1 H, J ) 7.6, 5.1 Hz), 4.08 (qd, 1 H, J ) 6.4,
3.1 Hz), 4.21 (ddd, 1 H, J ) 10.0, 7.1, 3.0 Hz); 13C NMR (75
MHz) δ 9.6, 18.2, 24.4, 35.7, 68.0, 79.2, 81.5, 215.8; IR (film)
3449, 2972, 2934, 2878, 1755, 1460, 1379, 1186, 1069 cm-1; MS
(ES) 181 [M + Na]+ (100%), 159 [M + H]+. Anal. Calcd for
C8H14O3: C, 60.74; H, 8.92. Found: C, 60.91; H, 9.08.
Synthesis of (-)-(2S,3S,4S,5S)-2-(tert-Butyldimethylsilyloxy-
methyl)-3,4-epoxy-5-pentyl-4-(p-tolylsulfonyl)tetrahydrofuran, 37:
From sulfonyl dihydrofuran 10a (291 mg, 0.66 mmol) in THF (6.6
mL) and KOOt-Bu (2.0 equiv in 6.6 mL of THF), according to the
general procedure described in the Supporting Information (50 min),
sulfonyl oxirane 37 was obtained as a single isomer. Purification
by column chromatography (50-60% CH2Cl2-hexane) afforded
Jacobsen Epoxidation of Tributylsilyloxy Sulfinyl Diene 24a:
From a cold solution (0 °C) of hydroxy sulfinyl diene 24a (25 mg,
0.05 mmol) in a 1:1 mixture of CH2Cl2/MeOH (0.5 mL), NH4OAc
(4.2 mg, 0.05 mmol, 1.0 equiv), (R,R)-JC (1.7 mg, 0.003 mmol,
0.05 equiv), and H2O2 (49 µL), according to the general procedure
described in the Supporting Information (for 4 days), and after two
additional loads of reagents, an inseparable 96:4 mixture of
monoepoxides 28 and 29 (21 mg, 78%) was obtained as a colorless
oil. Partial data for 28 (from the mixture): Rf 0.21 (10%
EtOAc-hexane); 1H NMR (300 MHz) δ 0.33 (m, 6 H), 0.83 (t, 9
H, J ) 6.8 Hz), 0.87 (t, 3 H, J ) 7.3 Hz), 1.06-1.27 (m, 12 H),
1.35 (d, 3 H, J ) 5.1 Hz), 1.49-1.72 (m, 2 H), 2.42 (s, 3 H), 2.99
(qd, 1 H, J ) 5.1, 2.0 Hz), 3.91 (dd, 1 H, J ) 9.1, 2.0 Hz), 4.43
(dd, 1 H, J ) 8.1, 3.7 Hz), 6.32 (d, 1 H, J ) 9.1 Hz), 7.31 (d, 2 H,
J ) 7.8 Hz), 7.71 (d, 2 H, J ) 8.3 Hz); 13C NMR (75 MHz) δ
10.3, 13.2 (3 C), 13.7 (3 C), 17.3, 21.6, 25.2 (3 C), 26.5 (3 C),
31.6, 54.7, 56.5, 70.7, 128.5 (2 C), 129.9 (2 C), 136.5, 140.5, 144.6,
149.2; IR (film) 2956, 2926, 2869, 1642, 1595, 1464, 1409, 1374,
1320, 1300, 1172, 1147, 1113, 1088, 1063, 1016, 886, 836, 811,
730, 668 cm-1; MS (ES) 517 [M + Na]+ (100%), 495 [M + H]+.
Desilylation with TBAF and Cyclization with CSA of Monoe-
poxides 28/29: From a cold solution (0 °C) of the mixture of
monoepoxides 28 and 29 (17 mg, 0.03 mmol) in THF (0.3 mL), 1
M solution of TBAF (27 mg, 0.09 mmol, 2.5 equiv) in THF, and
CSA (3.2 mg, 0.01 mmol, 0.4 equiv) in CH2Cl2 (0.1 mL), according
to the general procedure described in the Supporting Information
(for 15 h), and after purification by column chromatography
(20-50% EtOAc-hexane), 30 (1 mg, 9%) and 21 (10 mg, 90%)
were obtained as colorless oils.
37 (290 mg, 97%) as a colorless oil. Data for 37: Rf 0.23 (10%
1
EtOAc-hexane); [R]20 -9.2 (c ) 2.02); H NMR (300 MHz) δ
D
0.07 (s, 3 H), 0.08 (s, 3 H), 0.80 (t, 3 H, J ) 6.6 Hz), 0.90 (s, 9 H),
1.06-1.40 (m, 8 H), 2.44 (s, 3 H), 3.66 (dd, 1 H, J ) 11.0, 5.9
Hz), 3.71 (dd, 1 H, J ) 10.7, 3.9 Hz), 3.95 (s, 1 H), 3.99 (dd, 1 H,
J ) 5.6, 3.9 Hz), 4.57 (t, 1 H, J ) 5.5 Hz), 7.35 (d, 2 H, J ) 8.1
Hz), 7.79 (d, 2 H, J ) 8.3 Hz); 13C NMR (75 MHz) δ -5.6 (2 C),
13.8, 18.2, 21.6, 22.3, 24.9, 25.8 (3 C), 26.8, 29.7, 31.5, 63.1, 65.4,
75.0, 76.5, 77.8, 129.0 (2 C), 129.7 (2 C), 133.9, 145.7; IR (film)
2952, 2930, 2857, 1597, 1494, 1464, 1382, 1334, 1303, 1256, 1161,
1091, 838, 814, 780, 705, 665 cm-1; MS (ES) 477 [M + Na]+
(100%), 455 [M + H]+. Anal. Calcd for C23H38O5SSi: C, 60.75;
H, 8.42; S, 7.05. Found: C, 60.51; H, 8.69; S, 6.83.
Synthesis of (-)-(2S,5R)-5-(tert-Butyldimethylsilyloxymethyl)-
2-pentyl-3-oxotetrahydrofuran, 38: From sulfonyl oxirane 37 (92
mg, 0.20 mmol) in Et2O (1.0 mL) and MgI2 (3.6 mL from a ca.
0.2 M solution in Et2O, 0.71 mmol, 3.5 equiv), according to the
general procedure described in the Supporting Information (for 3 h),
and after chromatography (60-70% CH2Cl2-hexane), ketone 38
(58mg,97%)wasobtained.Datafor38:Rf 0.31(10%EtOAc-hexane);
1
[R]20 -64.3 (c ) 1.24); H NMR (300 MHz) δ 0.02 (s, 3 H),
D
0.03 (s, 3 H), 0.84 (s, 9 H), 0.85 (t, 3 H, J ) 6.8 Hz), 1.23-1.66
(m, 8 H), 2.42 (dd, 1 H, J ) 18.1, 4.6 Hz), 2.51 (dd, 1 H, J )
17.8, 7.8 Hz), 3.64 (dd, 1 H, J ) 10.8, 2.8 Hz), 3.86 (dd, 1 H, J )
10.7, 3.2 Hz), 3.99 (dd, 1 H, J ) 7.4, 4.6 Hz), 4.41 (ddt, 1 H, J )
7.7, 4.5, 3.1 Hz); 13C NMR (75 MHz) δ -5.7, -5.6, 14.0, 18.1,
22.4, 24.9, 25.7 (3 C), 31.6, 31.9, 38.3, 66.6, 75.4, 80.1, 216.4; IR
(film) 2952, 2930, 2855, 1759, 1463, 1406, 1361, 1256, 1177, 1091,
1015, 837, 775 cm-1; MS (ES) 323 [M + Na]+ (100%), 301 [M +
Nucleophilic Epoxidation of Sulfonyl Dihydrofuran 21: From
sulfonyl dihydrofuran 21 (57 mg, 0.19 mmol) in THF (2.0 mL)
and KOOt-Bu (2.0 equiv in 2.0 mL of THF), according to the
general procedure described in the Supporting Information (for 7 h),
a 97:3 mixture of sulfonyl oxiranes 31 was obtained. Purification
by column chromatography (10-50% EtOAc-hexane) afforded
180 J. Org. Chem. Vol. 74, No. 1, 2009

Katsuki-Jacobsen Oxidation-Epoxidation
H]+. Anal. Calcd for C16H32O3Si: C, 63.95; H, 10.73. Found: C,
64.19; H, 10.44.
H]+. Anal. Calcd for C23H38O4Si: C, 67.94; H, 9.42. Found: C,
68.16; H, 9.67.
Synthesis of (+)-(2S,3S,5R)-3-Phenylcarbonyloxy-5-hydroxy-
methyl-2-pentyltetrahydrofuran, 42: From benzoate 41 (114 mg,
0.28 mmol) in MeOH (2.8 mL) and Dowex resin (157 mg),
according to the general procedure described in the Supporting
Information, and after column chromatography (5-10%
EtOAc-CH2Cl2), alcohol 42 (80 mg, 96%) was obtained as a
Synthesis of (+)-(2S,3S,5R)-5-(tert-Butyldimethylsilyloxymethyl)-
2-pentyltetrahydrofuran-3-ol, 40, and (2S,3R,5R)-5-(tert-Butyldi-
methylsilyloxymethyl)-2-pentyltetrahydrofuran-3-ol, 39: From ke-
tone 38 (97 mg, 0.32 mmol) in THF (3.2 mL) and L-Selectride
(0.96 mL 0.96 mmol, 1.0 M in THF, 3.0 equiv), according to the
general procedure described in the Supporting Information, and after
column chromatography (1-5% EtOAc-CH2Cl2), 40 (10 mg, 12%)
colorless oil. Data for 42: Rf 0.14 (10% EtOAc-CH2Cl2); [R]20
D
1
+36.2 (c ) 6.76); H NMR (300 MHz) δ 0.82 (t, 3 H, J ) 6.8
and 39 (87 mg, 88%) were obtained as colorless oils. Data for 39:
Hz), 1.22-1.72 (m, 8 H), 1.90 (t, 1 H, J ) 6.3 Hz), 2.14 (m, 2 H),
3.53 (dt, 1 H, J ) 11.5, 5.6 Hz), 3.75 (ddd, 1 H, J ) 11.7, 6.1, 3.2
Hz), 4.06 (ddd, 1 H, J ) 9.5, 6.1, 3.3 Hz), 4.37 (tdd, 1 H, J ) 8.1,
5.6, 3.2 Hz), 5.56 (dd, 1 H, J ) 6.1, 3.2 Hz), 7.44 (t, 2 H, J ) 7.6
Hz), 7.56 (tt, 1 H, J ) 7.6, 1.2 Hz), 8.03 (dd, 2 H, J ) 8.2, 1.2
Hz); 13C NMR (75 MHz) δ 13.9, 22.5, 26.0, 29.4, 31.9, 34.8, 64.6,
75.9, 77.2, 77.7, 81.3, 128.5 (2 C), 129.6 (2 C), 130.1, 133.2, 165.9;
IR (film) 3435, 3063, 3033, 2930, 2860, 1716, 1603, 1584, 1491,
1453, 1355, 1313, 1274, 1173, 1114, 1069, 1025, 903, 804, 711,
686, 665 cm-1; MS (ES) 315 [M + Na]+, 293 [M + H]+ (100%).
Anal. Calcd for C17H24O4: C, 69.84; H, 8.27. Found: C, 69.65; H,
8.49.
1
Rf 0.13 (5% EtOAc-CH2Cl2); [R]20 +11.1 (c ) 1.50); H NMR
D
(300 MHz) COSY δ 0.03 (s, 6 H), 0.87 (m, 12 H), 1.23-1.64 (m,
9 H), 1.95 (dd, 1 H, J ) 13.6, 7.2 Hz), 2.02 (ddd, 1 H, J ) 13.5,
8.5, 4.2 Hz), 3.57 (dd, 1 H, J ) 10.7, 4.2 Hz), 3.65 (dd, 1 H, J )
10.7, 4.2 Hz), 3.75 (td, 1 H, J ) 6.8, 2.7 Hz), 4.18-4.26 (m, 2 H);
13C NMR (75 MHz) HSQC δ -5.4 (2 C), 14.0, 18.3, 22.6, 25.9 (3
C), 26.0, 28.9, 32.0, 37.2, 65.6, 73.5, 77.1, 82.8; IR (film) 3413,
2955, 2929, 2858, 1463, 1471, 1387, 1361, 1255, 1185, 1132, 1088,
1028, 1004, 938, 837, 813, 777, 662 cm-1; MS (ES) 325 [M +
Na]+, 303 [M + H]+ (100%). Anal. Calcd for C16H34O3Si: C, 63.52;
H, 11.33. Found: C, 63.26; H, 11.08. Data for 40: Rf 0.35 (5%
EtOAc-CH2Cl2); 1H NMR (300 MHz) δ 0.098 (s, 6 H), 0.86 (t, 3
H, J ) 6.5 Hz), 0.91 (s, 9 H), 1.23-1.40 (m, 8 H), 1.82 (dd, 1 H,
J ) 13.7, 2.4 Hz), 2.32 (ddd, 1 H, J ) 13.9, 9.5, 5.6 Hz), 3.52 (dd,
1 H, J ) 10.7, 1.7 Hz), 3.84 (dd, 1 H, J ) 11.0, 2.2 Hz), 3.89-3.95
(m, 2 H), 4.07 (d, 1 H, J ) 11.0 Hz), 4.20 (dd, 1 H, J ) 9.8, 2.2
Hz); 13C NMR (75 MHz) δ -5.6, -5.5, 14.0, 18.5, 22.6, 25.7,
25.9 (3 C), 31.8, 33.5, 35.5, 66.0, 75.1, 77.4, 88.4; IR (film) 3433,
2955, 2930, 2854, 1462, 1361, 1254, 1092, 1042, 1004, 938, 837,
778 cm-1; MS (ES) 325 [M + Na]+, 303 [M + H]+ (100%). Anal.
Calcd for C16H34O3Si: C, 63.52; H, 11.33. Found: C, 63.77; H,
11.66.
Synthesis of (+)-(2S,3S,5R)-3-Phenylcarbonyloxy-5-formyl-2-
pentyltetrahydrofuran, 43:20a From (COCl)2 (16 µL, 23 mg, 0.18
mmol, 3.5 equiv) in CH2Cl2 (0.72 mL), DMSO (18 µL, 20 mg,
0.26 mmol, 5.0 equiv) in CH2Cl2 (0.26 mL), alcohol 42 (15 mg,
0.05 mmol) in CH2Cl2 (0.4 mL), and Et3N (46 µL, 33 mg, 0.33
mmol, 6.5 equiv), according to the general procedure described in
the Supporting Information (for 1 h, 30 min), and after column
chromatography (0-5% EtOAc-CH2Cl2), aldehyde 43 (11 mg,
80%) was obtained as a colorless oil. Data for 43: Rf 0.27 (5%
EtOAc-CH2Cl2); [R]20D +43.7 (c ) 1.04); 1H NMR (300 MHz) δ
0.83 (t, 3 H, J ) 7.1 Hz), 1.24-1.48 (m, 6 H), 1.61-1.81 (m, 2
H), 2.38 (m, 2 H), 4.03 (ddd, 1 H, J ) 7.6, 6.0, 3.4 Hz), 4.54 (td,
1 H, J ) 8.3, 1.5 Hz), 5.56 (q, 1 H, J ) 3.2 Hz), 7.44 (t, 2 H, J )
7.8 Hz), 7.58 (t, 1 H, J ) 7.3 Hz), 8.02 (dd, 2 H, J ) 8.5, 1.5 Hz),
9.73 (d, 1 H, J ) 1.7 Hz); 13C NMR (75 MHz) δ 13.9, 22.4, 25.9,
29.0, 31.7, 34.6, 74.5, 80.9, 83.2, 128.5 (2 C), 129.7 (3 C), 133.4,
165.8, 202.0; IR (film) 2927, 2857, 1723, 1603, 1584, 1453, 1377,
1313, 1272, 1174, 1112, 1027, 760, 711 cm-1; MS (ES) 291 [M +
H]+.
Synthesis of (+)-(2S,3S,5R)-5-(tert-Butyldimethylsilyloxymethyl)-
3-phenylcarbonyloxy-2-pentyltetrahydrofuran, 41: From alcohol
39 (97 mg, 0.32 mmol) in CH2Cl2 (3.2 mL), benzoic acid (86 mg,
0.71 mmol, 2.2 equiv), DCC (132 mg, 0.64 mmol, 2.0 equiv), and
DMAP (2 mg, 0.02 mmol, 0.05 equiv), according to the general
procedure described in the Supporting Information, and after column
chromatography (5-10% EtOAc-hexane), benzoate 41 (120 mg,
92%) was obtained as a colorless oil. Data for 41: Rf 0.18 (10%
EtOAc-hexane); [R]20D +22.2 (c ) 1.74); 1H NMR (300 MHz) δ
0.06 (s, 6 H), 0.82 (t, 3 H, J ) 6.9 Hz), 0.89 (s, 9 H), 1.22-1.67
(m, 8 H), 2.13 (ddd, 1 H, J ) 14.1, 7.0, 1.0 Hz), 2.27 (ddd, 1 H,
J ) 13.8, 8.5, 5.0 Hz), 3.63 (dd, 1 H, J ) 10.7, 3.9 Hz), 3.72 (dd,
1 H, J ) 10.7, 4.2 Hz), 4.05 (ddd, 1 H, J ) 9.3, 6.1, 3.4 Hz), 4.30
(ddd, 1 H, J ) 12.5, 8.3, 4.1 Hz), 5.53 (t, 1 H, J ) 3.7 Hz), 7.43
(t, 2 H, J ) 7.6 Hz), 7.55 (t, 1 H, J ) 7.5 Hz), 8.03 (dd, 2 H, J )
7.1, 1.5 Hz); 13C NMR (75 MHz) δ -5.4, -5.3, 14.0, 18.3, 22.5,
25.9 (3 C), 26.0, 29.4, 31.8, 35.1, 65.5, 76.3, 77.6, 81.8, 128.4 (2
C), 129.6 (2 C), 130.2, 133.1, 166.0; IR (film) 3064, 2952, 2929,
2858, 1722, 1603, 1469, 1463, 1452, 1315, 1273, 1114, 1094, 1027,
836, 778, 711 cm-1; MS (ES) 429 [M + Na]+ (100%), 407 [M +
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, CSIC-
FSE for doctoral fellowships to A.C. and I.C., and a postdoctoral
contract to I.O.
Supporting Information Available: Experimental proce-
dures and characterization for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801803M
J. Org. Chem. Vol. 74, No. 1, 2009 181