Metal-catalyzed oxidation and epoxidation of α-hydroxy vinyl and dienyl sulfoxides

Article abstract of DOI:10.1021/jo052244d

Treatment of acyclic α-hydroxyalkyl α,β-unsaturated sulfoxides with t-BuOOH/VO(acac)₂ results in rapid oxidation to the unsaturated sulfones followed by an unusual regio- and stereoselective epoxidation at the unsaturated sulfones; this methodo

Full text of DOI:10.1021/jo052244d

Metal-Catalyzed Oxidation and Epoxidation of r-Hydroxy Vinyl
and Dienyl Sulfoxides
Roberto Ferna´ndez de la Pradilla,* Alejandro Castellanos, Jorge Ferna´ndez,
Milagros Lorenzo, Pilar Manzano, Paloma Me´ndez, Julia´n Priego, and Alma Viso
Instituto de Qu´ımica Orga´nica, CSIC, Juan de la CierVa, 3, 28006 Madrid, Spain
iqofp19@iqog.csic.es
ReceiVed October 28, 2005
Treatment of acyclic R-hydroxyalkyl R,â-unsaturated sulfoxides with t-BuOOH/VO(acac)2 results in rapid
oxidation to the unsaturated sulfones followed by an unusual regio- and stereoselective epoxidation at
the unsaturated sulfones; this methodology has been applied to the preparation of carbohydrate-like
fragments.
SCHEME 1
Introduction
In recent years, we have been studying in depth the nucleo-
philic epoxidation of alkenyl sulfoxides, a general route to
enantiopure sulfinyl and sulfonyl oxiranes,1 that are versatile
synthetic intermediates.2 In the course of these studies, we
examined the nucleophilic epoxidation of hydroxy dienyl
sulfoxides A (Scheme 1) with the expectation that monoepoxides
D or E, perceived as suitable precursors to unusual carbohydrate
fragments,3 would be obtained. In contrast, tetrahydrofurans C
were formed in moderate yields by a completely different
reaction pathway.4 At this stage, a literature survey revealed
isolated examples of metal-catalyzed electrophilic epoxidations
of R-hydroxyalkyl R,â-unsaturated esters and ketones,5 and these
conditions were identified as a straightforward option to access
the desired oxiranes D or E from readily available hydroxy
dienes A. In this paper, we describe in full our studies on the
facile and highly stereo- and regioselective epoxidation of
hydroxy vinyl and dienyl sulfones to produce sulfonyl oxiranes
E.6
Metal-Catalyzed Epoxidation of Alkenyl and Dienyl
Sulfones
(1) (a) Ferna´ndez de la Pradilla, R.; Castro, S.; Manzano, P.; Priego, J.;
Viso, A. J. Org. Chem. 1996, 61, 3586-3587. (b) Ferna´ndez de la Pradilla,
R.; Castro, S.; Manzano, P.; Mart´ın-Ortega, M.; Priego, J.; Viso, A.
Rodr´ıguez, A.; Fonseca, I. J. Org. Chem. 1998, 63, 4954-4966. (c)
Ferna´ndez de la Pradilla, R.; Ferna´ndez, J.; Manzano, P.; Me´ndez, P.; Priego,
J.; Tortosa, M.; Viso, A.; Mart´ınez-Ripoll, M.; Rodr´ıguez, A. J. Org. Chem.
2002, 67, 8166-8177. (d) For the highly selective preparation of spirocyclic
bis-sulfinyl oxiranes by a related methodology, see: Aggarwal, V. K.;
Barrell, J. K.; Worrall, J. M.; Alexander, R. J. Org. Chem. 1998, 63, 7128-
7129.
The substrates selected for this study (1a-g, 2a-c, 3, 4a,b,
5, 6a-d, and 7a-c) are shown below and were prepared by
standard procedures (see the Supporting Information). These
substrates were selected so as to provide useful information on
the scope of the reaction with regard to the nature and size of
the substituents, the functionality, the geometry of the substrates,
etc. Table 1 summarizes the results obtained for simple E and
10.1021/jo052244d CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/21/2006
J. Org. Chem. 2006, 71, 1569-1575
1569

Ferna´ndez de la Pradilla et al.
TABLE 1. Metal-Catalyzed Oxidation/Epoxidation of Hydroxy Alkenyl Sulfoxides and Sulfides
entry
substrate
conditions
anti
syn
yielda (%)
1
2
1a
1b
1c
1d
1e
1f
1g
2a
2b
2c
3
10% VO(acac)2, 2.5 equiv of t-BuOOH, 3 days
15% VO(acac)2, 3.0 equiv of t-BuOOH, 28 h
25% VO(acac)2, 4.0 equiv of t-BuOOH, 132 h
65% VO(acac)2, 9.0 equiv of t-BuOOH, 56 h
25% VO(acac)2, 8.5 equiv of t-BuOOH, 4 days
15% VO(acac)2, 7.0 equiv of t-BuOOH, 72 h
30% VO(acac)2, 7.0 equiv of t-BuOOH, 86 h
25% VO(acac)2, 5.5 equiv of t-BuOOH, 85 h
15% VO(acac)2, 5.0 equiv of t-BuOOH, 6 h
20% VO(acac)2, 6.0 equiv of t-BuOOH, 20 h
15% VO(acac)2, 3.0 equiv of t-BuOOH, 4 h
8a
8b
8c
8d
8e
76
76
84
65
54
60
44
80
87
72
91
3
4b
5
6
9f
9g
7
8c
9
10a
10b
10c
12
10
11
a Combined yields of pure products after column chromatography. b Alkenyl sulfone 1d′′ (18%) was also isolated. c The related keto sulfonyl oxirane
10a′ (39%) was also isolated.
Z alkenyl sulfoxides. All cases examined proceeded by an initial
very fast oxidation to the alkenyl sulfones 1′′ and 2′′ with 5%
VO(acac)2 and 1.5 equiv of t-BuOOH regardless of the relative
configuration of the substrates. Subsequent additions of catalyst
and t-BuOOH were performed when necessary (TLC) to enable
reaction completion, generally with rather slow kinetics, prob-
ably related with the known inactivation of the catalyst by
t-BuOH or adventitious water.7 The initial stage of this
investigation was carried out on simple hydroxy vinyl sulfoxide
1a (Table 1, entry 1) that gave a good overall yield of anti
sulfonyl oxirane 8a as a single isomer. Encouraged by this result,
we set out to explore the scope of this process. Thus, substrates
1b and 1c with bulkier R1 substituents cleanly afforded anti
oxiranes 8b and 8c, respectively, in good yields (Table 1, entries
2 and 3). Sulfinyl chlorohydrin 1d was only marginally reactive
and led to a fair yield of oxirane 8d along with a substantial
amount of sulfonyl chlorohydrin 1d′′ (18%) (Table 1, entry 4).
(2) For a review on the preparation and applications of R-oxy sulfones,
including sulfonyl oxiranes, see: (a) Chemla, F. J. Chem. Soc., Perkin Trans.
1 2002, 275-299. For other reviews on aspects of the synthesis and
reactivity of sulfinyl and sulfonyl oxiranes, see: (b) Satoh, T.; Yamakawa,
K. Synlett 1992, 455-468. (c) Satoh, T. Chem. ReV. 1996, 96, 3303-3325.
For recent references on applications of sulfinyl and sulfonyl oxiranes,
see: (d) Mori, Y.; Hayashi, H. J. Org. Chem. 2001, 66, 8666-8668. (e)
Satoh, T.; Taguchi, D.; Kurabayashi, A.; Kanoto, M. Tetrahedron 2002,
58, 4217-4224. (f) Mori, Y.; Hayashi, H. Tetrahedron 2002, 58, 1789-
1797. (g) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996,
118, 8158-8159. (h) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem.
Soc. 1997, 119, 4557-4558. (i) For a recent application of these building
blocks within synthetic studies toward yessotoxin and adriatoxin, see: Mori,
Y.; Takase, T.; Noyori, R. Tetrahedron Lett. 2003, 44, 2319-2322. (j) For
an application to the synthesis of a fragment of ciguatoxin, see: Inoue, M.;
Yamashita, S.; Tatami, A.; Miyazaki, K.; Hirama, M. J. Org. Chem. 2004,
69, 2797-2804. (k) For an application to the synthesis of a fragment of
gambierol, see: Furuta, H.; Hase, M.; Noyori, R.; Mori, Y. Org. Lett. 2005,
7, 4061-4064.
(5) (a) Adam, W.; Braun, M.; Griesbeck, A.; Lucchini, V.; Staab, E.;
Will, B. J. Am. Chem. Soc. 1989, 111, 203-212. (b) Bailey, M.; Staton, I.;
Ashton, P. R.; Marko´, I. E.; Ollis, W. D. Tetrahedron: Asymmetry 1991,
2, 495-509.
(6) For a preliminary communication, see: Ferna´ndez de la Pradilla, R.;
Me´ndez, P.; Priego, J.; Viso, A. J. Chem. Soc., Perkin Trans. 1 1999, 1247-
1249.
(7) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136-6137. (b) Rossiter, B. E.; Verhoeven, T. R.; Sharpless, K. B.
Tetrahedron Lett. 1979, 20, 4733-4736. (c) Mihelich, E. D. Tetrahedron
Lett. 1979, 20, 4729-4732.
(3) For reviews on the synthesis of carbohydrate derivatives from acyclic
precursors, see: (a) Ager, D. J.; East, M. B. Tetrahedron 1993, 49, 5683-
5765. (b) Ager, D. J.; East, M. B. Tetrahedron 1992, 48, 2803-2894.
(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.
1570 J. Org. Chem., Vol. 71, No. 4, 2006

Oxidation/Epoxidation of Hydroxyalkyl Unsaturated Sulfoxides
TABLE 2. Metal-Catalyzed Oxidation/Epoxidation of Hydroxy Dienyl Sulfoxides
entry
substrate
conditions
diene
anti
13a
13b (86)
13b (99)
13b (72)
13b (99)
13c
ketone
yielda (%)
1
2
3
4
5
6
7b
6a
6b
6b
6b
6b
6c
6d
20% VO(acac)2, 3.0 equiv of t-BuOOH, 7 h
15% VO(acac)2, 2.5 equiv of t-BuOOH, 4 days
15% VO(acac)2, 2.5 equiv of t-BuOOH, Tol, 4 days
15% VO(acac)2, 5.0 equiv of t-BuOOH, 1 day
30% VO(acac)2, 3.5 equiv of t-BuOOH, Tol, 2 days
15% VO(acac)2, 3.0 equiv of t-BuOOH, 6 h
10% VO(acac)2, 3.0 equiv of t-BuOOH, 90 min
73
54
55
87
70
86
35
14b (14)
6b′′ (1)
14b (28)
14b (1)
6d′′
a Combined yields of pure products after column chromatography. b Sulfonyl diene 6d′′ was isolated from a complex mixture of products.
Similarly, tert-butylsulfinyl substrate 1e produced a fair yield
of oxirane 8e (Table 1, entry 5).
prone to overoxidation at the benzylic position.8 While at this
stage we did not pursue the optimization of this particular case,
the results found for benzylic diene 6b discussed below suggest
that by carefully monitoring the reaction and with minor
experimental modifications this overoxidation should be control-
lable. Two additional examples of Z geometry were also
examined with excellent results (Table 1, entries 9 and 10) with
alkenyl sulfides being also adequate substrates for this process.
Finally, the oxidation/epoxidation protocol was applied to
tetrasubstituted alkenyl sulfoxide 3 to produce anti oxirane 12
as a single isomer and in excellent yield (Table 1, entry 11).
To probe if cyclic derivatives were suitable substrates,
cyclopentenyl and cyclohexenyl sulfides 4a and 4b were
subjected to the reaction conditions. In both cases, oxidation to
the R-hydroxy alkenyl sulfones took place rapidly, but even
under forcing conditions, we could not even detect R-hydroxy
sulfonyl oxiranes. On the other hand, γ-hydroxy vinyl sulfoxide
5 was also tested under these conditions to produce a complex
mixture of products derived from oxidation at sulfur and at the
allylic hydroxyl without epoxidation. These results point out
some limitations of the methodology.
The structure and geometry of these oxiranes were derived
1
from their H and 13C NMR spectra with many of them being
known compounds. The syn stereochemistry attributed to 9f is
based on a detailed comparison of its spectral data with that of
very closely related compounds described in the literature.9
The viability and regioselectivity of this novel epoxidation
for simple sulfinyl and sulfonyl dienols 6 was then examined,
and the results obtained are shown in Table 2. Thus, ethyl-
substituted dienol 6a smoothly led to anti sulfonyl oxirane 13a
in good yield (Table 2, entry 1). In contrast, dienol 6b was less
reactive and gave substantial amounts of keto oxirane 14b that
was independently prepared by oxidation of 13b with PCC (see
the Supporting Information). The use of toluene diminished both
the rate of epoxidation and the rate of overoxidation, and long
reaction times brought about also substantial decomposition of
these labile vinyl oxiranes (Table 2, entries 2 and 3). Entries 4
In contrast to the above results, phenyl-substituted substrates
1f and 1g gave exclusively syn oxiranes 9f and 9g in fair yields
(Table 1, entries 6 and 7), indicating that a strong 1,3-allylic
strain is the prevailing element of stereocontrol in these cases
(see below). At this stage, we chose to examine the influence
of the geometry of the substrate on this process. Entry 8 shows
that benzylic alcohol 2a is also an adequate substrate, albeit
(8) Itoh, T.; Jitsukawa, K.; Kaneda, K.; Teranishi, S. J. Am. Chem. Soc.
1979, 101, 159-169.
(9) Jackson, R. F. W.; Standen, S. P.; Clegg, W.; McCamley, A. J. Chem.
Soc., Perkin Trans. 1 1995, 141-148.
J. Org. Chem, Vol. 71, No. 4, 2006 1571

Ferna´ndez de la Pradilla et al.
TABLE 3. Metal-Catalyzed Oxidation/Epoxidation of Hydroxy Trienyl Sulfoxides
entry
substrate
conditions
triene
7a′′
7a′′ (70)
7a′′ (50)
anti
anti-anti
syn-anti
yielda (%)
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7b
7b
7b
5% VO(acac)2, 1.3 equiv of aq t-BuOOH, 15 min
20% Ti(O-i-Pr)4, 3.0 equiv of aq t-BuOOH, CH2Cl2, 5 days
20% VO(acac)2, 3.0 equiv of aq t-BuOOH, 5 days
10% VO(acac)2, 5.0 equiv of t-BuOOH, 4 h
15% VO(acac)2, 9.0 equiv of t-BuOOH, 22 h
15% VO(acac)2, 5.0 equiv of t-BuOOH, 9 h
25% Ti(O-i-Pr)4, 4.0 equiv of t-BuOOH, CH2Cl2, 20 h
1.2 equiv Ti(O-i-Pr)4, 1.6 equiv of (-)-DET,
6.0 equiv of t-BuOOH, CH2Cl2, 17 h
70
39
78
65
62
65
40
91
15a (30)
15a (50)
15a
15a (28)
16a (72)
16b (77)
16b (36)
17b (23)
17b (64)
7b′′
9b
7c
15% VO(acac)2, 4.5 equiv of t-BuOOH, 24 h
16c
36
a Combined yields of pure products after column chromatography. b Bis oxirane 16c was isolated with difficulty from a complex mixture of products.
and 5 gather the improved conditions for the desired transforma-
tion that involve either a larger excess of t-BuOOH or of
catalyst, if toluene is used. gem-Dimethyl-substituted dienol 6c
gave a good yield of oxirane 13c. Finally, considerable
experimentation was devoted to the reaction of dienol 6d,
bearing a Me substituent at the diene terminus. Despite these
efforts, we could only isolate low yields of sulfonyl diene 6d′′
at relatively short reaction times and from a rather complex
mixture.10
substituent at the hydroxylic carbon, gave exclusively bis
oxiranes 16b and 17b by simultaneous epoxidation at both sites
(Table 3, entry 6). Catalysis by Ti(O-i-Pr)4 resulted in a poor
yield of a 36:64 mixture of bis oxiranes 16b and 17b with
reversal of selectivity of epoxidation at the allylic alcohol,11
(Table 3, entry 7) and an attempt at carrying out the “asym-
metric” epoxidation with t-BuOOH/ Ti(O-i-Pr)4/(-)-DET re-
sulted in just oxidation to the trienyl sulfone (Table 3, entry 8).
Finally, trienol 7c gave rise to complex mixtures of regioiso-
meric monoepoxides at short and intermediate reaction times
and to a low yield of a very sensitive bis oxirane 16c, as shown
in entry 9 of Table 3.
Encouraged by the regioselectivity found for most dienes
tested (6a-c), we decided to examine the behavior of the more
challenging trienols 7 that have an additional allylic alcohol
that may undergo epoxidation, and the results obtained are
shown in Table 3. Throughout the previous studies on this
method we had observed that the rate of the initial oxidation to
sulfone was consistently high for different presentations of
commercial t-BuOOH. On the other hand, the rate of the
epoxidation varied widely with the aqueous reagent being
slowest and commercially available anhydrous solutions in
hydrocarbons being fastest. Thus, our initial experiments were
conducted with 70% aqueous t-BuOOH, and this allowed for
smooth oxidation of trienol 7a to sulfone 7a′′ (Table 3, entry
1). Catalysis by Ti(O-i-Pr)4 was also tested and a small amount
of anti monoepoxide 15a was obtained in low yield (Table 3,
entry 2). A substantial increase in yield and a modest increase
in conversion to the desired monoepoxide 15a was observed
with VO(acac)2 (Table 3, entry 3). Optimal conditions for
obtaining monoepoxide 15a entailed short reaction times and
an excess of anhydrous t-BuOOH in benzene as solvent (Table
3, entry 4). With a larger load of catalyst and t-BuOOH and
longer reaction times, a fair yield of the very sensitive bis
oxirane 16a was obtained as a single isomer, arising from
“normal” epoxidation of the allylic alcohol moiety of 15a (Table
3, entry 5). In contrast, trienol 7b, with an (E)-1′-propenyl
Synthetic Applications
Having studied in depth the scope and limitations of our
metal-catalyzed epoxidation of alkenyl and dienyl sulfones, we
focused our efforts on carrying out exploratory experiments to
probe the application of these intermediates to the preparation
of unnatural carbohydrates and tetrahydrofurans.3 Readily
available vinyl oxiranes 13a and 13b were selected at this stage
to examine the ozonolysis of the alkene that, at short reaction
times (5-7 min), gave excellent yields of the desired lactols
18a and 18b (Scheme 2) as ca. 90:10 mixtures of anomers.12
The oxidation of these lactols to the related lactones was then
tested, but all conditions explored failed and unreacted lactol
was recovered.13 In view of these results and seeking additional
structural evidence, lactols 18 were acetylated to provide
furanose derivatives 19a and 19b uneventfully. Finally, reduc-
tion of 18b with NaBH4 produced a good yield of epoxy diol
20.
(11) See references cited in: Adam, W.; Corma, A.; Reddy, T. I.; Renz,
M. J. Org. Chem. 1997, 62, 3631-3637.
(12) At long reaction times, other products, not fully identified, presum-
ably derived from overoxidation were obtained.
(10) For an excellent review on sulfonyl 1,3-dienes, see: Ba¨ckvall, J.-
E.; Chinchilla, R.; Na´jera, C.; Yus, M. Chem. ReV. 1998, 98, 2291-2312.
For reports somewhat complimentary to our own results, see: (a) Urones,
J. G.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Bastida, A. J.; San Feliciano,
S. G.; D´ıez, D.; Goodman, J. M. Synlett 1998, 1361-1363. (b) Urones, J.
G.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; San Feliciano, S. G.; Coca,
R.; D´ıez, D. Synlett 1998, 1364-1365.
(13) These include O3 followed by an excess of H2O2, PCC/NaOAc,
I2/CaCO3, Dess-Martin, etc. (a) Corey, E. J.; Su, W.-G. J. Am. Chem. Soc.
1987, 109, 7534-7536. (b) Morikawa, T.; Nishiwaki, T.; Iitaka, Y.;
Kobayashi, Y. Tetrahedron Lett. 1987, 28, 671-674. (c) Valverde, S.;
Garc´ıa-Ochoa, S.; Mart´ın-Lomas, M. J. Chem. Soc., Chem. Commun. 1987,
1714-1715. (d) Corey, E. J.; Kang, M.-C.; Desai, M. C.; Ghosh, A. K.;
Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 649-651.
1572 J. Org. Chem., Vol. 71, No. 4, 2006

Oxidation/Epoxidation of Hydroxyalkyl Unsaturated Sulfoxides
TABLE 4. Attempts at Allylating Acetylated Lactols 19
yielda
(%)
entry
substrate
conditions
18
19
21
22
23
1
2
3
19b
19b
19b
5.0 equiv of BF3‚OEt2, CH2Cl2, 0 °C to rt, 15 h
5.0 equiv of BF3‚OEt2, CH3CN, 0 °C to rt, 36 h
2.0 equiv of EtOH, 3.0 equiv BF3‚OEt2, CH3CN,
0 °C to rt, 19 h
100 (14:86)
70
63
75
34 (100:0)
64 (81:19)
2 (60:40)
100 (94:6)
4
19b
2.0 equiv of SnCl4, CH2Cl2, -70 °C to rt, 14 h
23b
48
a Combined yields of pure products after column chromatography.
SCHEME 2
SCHEME 3
gave rise to a fair yield of a very interesting diallylated
tetrahydrofuran 23b albeit in low yield. A tentative reaction
pathway to account for the production of 23b is shown in
Scheme 3.
The Lewis acid catalyzed allylation of lactols related to 18
but lacking the sulfonyl oxirane moiety with allyl silanes is a
well-studied protocol to access substituted tetrahydrofurans.14
As observed before for the oxidation, these lactols turned out
to be notoriously unreactive under these conditions. Since these
transformations are also documented for anomeric acetates,15
the allylation of acetates 19a and 19b was attempted and the
results obtained are shown in Table 4. With BF3‚OEt2, all
conditions tested resulted in either recovery of starting material
(Table 4, entry 1) or production of a complex mixture of
deacetylated lactol 18, O-ethyl glycoside 21b (as an 81:19
mixture of diastereomers at the anomeric center), and just trace
amounts of the desired product 22 (Table 4, entry 2). Interest-
ingly, these acetates are unreactive even to glycosylation with
EtOH (Table 4, entry 3); therefore, ethyl glycoside 21b is likely
to be derived from acetate 19b by carboxylate reduction under
the reaction conditions. Substrate 19a, with a less bulky Et
substituent, gave equally disappointing results that largely
paralleled those of 19b. This unexpected lack of reactivity,16
prompted us to test SnCl4 as a Lewis acid promoter and this
In view of these results, we decided to examine the allylation
of open-chain epoxy aldehydes17 instead of the cyclic lactols,
and the results obtained are shown in Scheme 4. Thus, hydroxy
vinyl oxirane 13b was acetylated uneventfully to provide 24b
that underwent ozonolysis to produce aldehyde 25b in modest
yield, along with a relatively large amount of acid 26b. At this
stage we did not attempt to improve this transformation but
instead the BF3‚OEt2-catalyzed allylation of aldehyde 25b with
allyltributylstannane was explored leading to a separable 80:20
mixture of homoallylic alcohols 27b and 28b18 that should be
inmediate precursors to unusual hexoses upon, for instance,
ozonolysis. To rule out that these alcohols were isomeric due
to acetyl group migration, an 80:20 mixture of monoacetates
(16) Interestingly, hindered isopropylidenedioxy ribose acetates are
allylated under similar conditions, see: Wilcox, C. S.; Otoski, R. M.
Tetrahedron Lett. 1986, 27, 1011-1014.
(17) (a) Takeda, Y.; Matsumoto, T.; Sato, F. J. Org. Chem. 1986, 51,
4728-4731. (b) Howe, G. P.; Wang, S.; Procter, G. Tetrahedron Lett. 1987,
28, 2629-2632. (c) Wang, S.; Howe, G. P.; Mahal, R. S.; Procter, G.
Tetrahedron Lett. 1992, 33, 3351-3354. (d) Masamune, S.; Choy, W.;
Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1-30.
(e) For a leading reference on reagent controlled allylation of R,â-epoxy
aldehydes, see: Roush, W. R.; Straub, J. A.; VanNieuwenhze, M. S. J.
Org. Chem. 1991, 56, 1636-1648. (f) See also: Williams, D. R.; Brooks,
D. A.; Meyer, K. G.; Clark, M. P. Tetrahedron Lett. 1998, 39, 7251-7254.
(18) The stereochemistry of the new chiral center is assigned tentatively
in analogy with the results of Procter for nucleophilic additions to R,â-
epoxy aldehydes. See ref 17b.
(14) (a) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40-42. (b) Bru¨ckner,
C.; Holzinger, H.; Reissig, H.-U. J. Org. Chem. 1988, 52, 2450-2456. (c)
Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893-3901. (d) Pilli,
R. A.; Riatto, V. B. Tetrahedron: Asymmetry 2000, 11, 3675-3686.
(15) (a) Kozikowski, A. P.; Sorgi, K. L.; Wang, B. C. Xu, Z. Tetrahedron
Lett. 1983, 24, 1563-1566. (b) Minehan, T. G.; Kishi, Y. Tetrahedron Lett.
1997, 38, 6815-6818. For recent developments in this field, see: (c) Larsen,
C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc.
1999, 121, 12208-12209. (d) Smith, D. M.; Woerpel, K. A. Org. Lett.
2004, 6, 2063-2066.
J. Org. Chem, Vol. 71, No. 4, 2006 1573

Ferna´ndez de la Pradilla et al.
SCHEME 4
SCHEME 5
27b and 28b was acetylated to produce an inseparable mixture
of diacetates 29b and 30b.
Results and Discussion
philic epoxidation of these substrates. The application of this
methodology to the straightforward preparation of unusual
carbohydrate-like fragments through hydroxy sulfonyl diene
monoepoxides has been outlined. Additional applications of this
protocol are being examined in our laboratories.
The key findings of this study are the viability and stereo-
selectivity of the process for simple substrates and the regio-
selectivity found for some dienols and even trienols. These
findings can be tentatively rationalized by considering, after the
initial rapid oxidation at sulfur, a certain degree of coordination
between the sulfonyl oxygens and the metal to produce a cyclic
boatlike arrangement for the reactive conformers such as F and
G (Scheme 5).19 The precise balance of allylic 1,3-strain
between R1 and R2 or diaxial interactions (R1-O or R1-R3,
since both sulfonyl oxygens could in principle interact with the
metal) would dictate the favored reactive conformer. This
proposal accounts for the viability of the process and the lack
of reactivity of γ-hydroxy vinyl substrate 5 as well as for the
reversal of stereoselectivity found when R2 ) Ph (see Table 1)
due to an overwhelming allylic 1,3-strain between the conjugated
phenyl moiety (R2) and the ethyl substituent (R1) in conformer
F. The anti selectivity found for the Z isomers can be understood
similarly in terms of reactive conformers H and I (Scheme 5)
by considering the balance of allylic strain between R2 and p-Tol
(or O) and 1,3-diaxial interactions between R1 and oxygen (or
p-Tol).
Experimental Section
General Procedure for Oxidation/Epoxidation of Unsaturated
Sulfoxides with VO(acac)2/t-BuOOH. To a solution of the vinyl
or dienyl sulfoxide in anhydrous benzene (4 mL/mmol) was added
the catalyst, generally VO(acac)2 (0.01 M in benzene, 0.05 equiv).
After the solution was stirred for 5 min at rt, t-BuOOH was added
(0.5 M in benzene, typically 80% in t-BuOOt-Bu), and the mixture
changed from blue to red. A rapid oxidation to the alkenyl or dienyl
sulfone followed, and if necessary, additional amounts of VO(acac)2
and t-BuOOH were added at 1-3 h intervals or upon discoloration
of the mixture, until disappearance of the alkenyl sulfone. Upon
completion (TLC), the reaction was quenched with 1 M Na2S2O4
and diluted with EtOAc (8 mL/mmol), and the layers were
separated. The aqueous layer was extracted with EtOAc, and the
combined organic layers were washed with a saturated solution of
NaCl (4 mL/mmol), dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to give a crude product that
was purified by chromatography on silica gel using the appropriate
mixture of eluents. In most cases, especially those involving the
obtention of vinyl oxiranes, higher yields were obtained with 5 equiv
of t-BuOOH and purifying the crude products as soon as possible.
The precise rate of the epoxidation is highly dependent on the type
of commercial t-BuOOH used with the aqueous reagent being
slowest and the commercially available anhydrous reagents being
fastest.
Conclusions
To summarize, readily available acyclic hydroxy vinyl and
dienyl sulfoxides undergo a facile one-pot metal-catalyzed
oxidation and epoxidation with high diastereoselectivity that
complements in most cases the results obtained for the nucleo-
Synthesis of (-)-(1′R,2S,3S)-3-n-Butyl-2-(1′-hydroxy-2′,2′-
dimethylpropyl)-2-(p-tolylsulfonyl)oxirane, 8c. From a solution
of vinyl sulfoxide 1c1c (34 mg, 0.11 mmol) in C6H6 (1.7 mL) with
VO(acac)2 (0.25 equiv) and t-BuOOH (4.0 equiv) according to the
(19) For leading references on sulfonyl participation in chelated inter-
mediates, see: (a) Yakura, T.; Tanaka, K.; Iwamoto, M.; Nameki, M.; Ikeda,
M. Synlett 1999, 1313-1315. (b) Marcantoni, E.; Cingolani, S.; Bartoli,
G.; Bosco, M.; Sambri, L. J. Org. Chem. 1998, 63, 3624-3630.
1574 J. Org. Chem., Vol. 71, No. 4, 2006

Oxidation/Epoxidation of Hydroxyalkyl Unsaturated Sulfoxides
general procedure (132 h) was obtained epoxy sulfone 8c (31 mg,
84%) as a white solid after chromatography (50-100% CH2Cl2-
hexane). The data was identical to that found before.1c
Synthesis of (()-(1′S,2R,3S)-2-(1′-Hydroxypropyl)-3-phenyl-
2-(p-tolylsulfonyl)oxirane, 10b. From a solution of vinyl sulfoxide
2b1c (32 mg, 0.113 mmol) in C6H6 (2.0 mL) with VO(acac)2 (0.15
equiv) and t-BuOOH (5.0 equiv) according to the general procedure
(6 h) was obtained epoxy sulfone 10b (33 mg, 87%) after
chromatography (0-10% EtOAc-CH2Cl2). The data was identical
to that found before.1c
as a white solid recrystallized from Et2O-hexane. Long reaction
times (2-6 days) and the use of more than 3.5 equiv of t-BuOOH
led to increased amounts of ketone 14b; alternatively, short reaction
times (6-7 h) and lesser amounts of t-BuOOH substantially
diminish the rate of the reaction and significant amounts of dienyl
sulfone are produced. Under optimized conditions (30% VO(acac)2,
3.5 equiv of t-BuOOH, in toluene, 2 days), hydroxy oxirane 13b
was obtained along with small amounts of dienyl sulfone. Data for
13b: mp 132-134 °C; Rf ) 0.35 (30% EtOAc-hexane), 0.24 (1%
EtOAc-CH2Cl2); [R]20D ) +10.8 (c ) 0.60); 1H NMR (300 MHz)
δ 2.32 (s, 3 H), 3.80 (d, 1 H, J ) 10.6 Hz), 4.56 (d, 1 H, J ) 6.2
Hz), 4.94 (d, 1 H, J ) 10.6 Hz), 5.58 (d, 1 H, J ) 10.6 Hz), 5.71
(d, 1 H, J ) 17.1 Hz), 5.97 (ddd, 1 H, J ) 17.1, 10.7, 6.2 Hz),
6.97 (d, 2 H, J ) 8.1 Hz), 7.03-7.15 (m, 5 H), 7.22 (d, 2 H, J )
7.5 Hz); 13C NMR (50 MHz) δ 21.6, 62.1, 70.6, 78.0, 124.1, 125.8
(2 C), 127.7, 128.0 (2 C), 128.8, 128.9 (2 C), 129.1 (2 C), 133.9,
137.9, 144.6; IR (KBr) 3530, 3480, 2930, 1600, 1500, 1490, 1460,
1315, 1300, 1180, 1160, 1150, 1090, 1060, 1000, 940, 810, 780,
750, 710, 670 cm-1; MS (EI) 174, 157, 146, 139, 129, 118, 107,
91 (100), 77, 65, 57, 39; MS (APCI) 329 [M - 1]-, 155 (100).
Anal. Calcd for C18H18O4S: C, 65.43; H, 5.49; S; 9.70. Found: C,
65.48; H, 5.45; S, 9.65.
Epoxidation of (()-(2R,SS)-1-Cyclohexylidenyl-1-(p-tolyl-
sulfinyl)butan-2-ol, 3. From a solution of vinyl sulfoxide 3 (66
mg, 0.24 mmol) in C6H6 (0.4 mL) with VO(acac)2 (0.15 equiv)
and t-BuOOH (3.0 equiv) according to the general procedure (4 h)
was obtained epoxy sulfone 12 (66 mg, 91%) after chromatography
(0-50% EtOAc-hexane) as a white solid that was recrystallized
from CH2Cl2-hexane. Data for 12: mp 110-112 °C; Rf ) 0.30
1
(20% EtOAc-hexane); H NMR (200 MHz) δ 0.98 (t, 3 H, J )
7.4 Hz), 1.44-1.92 (m, 10 H), 1.92-2.02 (m, 2 H), 2.14 (m, 1 H),
2.43 (s, 3 H), 3.81-3.85 (m, 1 H), 7.34 (d, 2 H, J ) 7.9 Hz), 7.78
(d, 2 H, J ) 8.4 Hz); 13C NMR (50 MHz) δ 11.3, 21.7, 24.9 (2 C),
25.3, 26.2, 30.7, 31.1, 71.3, 72.3, 83.9, 128.5 (2 C), 129.8 (2 C),
136.2, 145.0. IR (KBr): 3511, 3434, 2939, 1289, 1145, 659 cm-1
;
MS (ES) 671 [2M + Na]+, 347 [M + Na]+ (100). Anal. Calcd for
C17H24O4S: C, 62.93; H, 7.46; S, 9.88. Found: C, 62.75; H, 7.35;
S, 10.12.
Acknowledgment. This research was supported by DGICYT
(BQU2003-02921) and CAM (GR/SAL/0823/2004). We thank
JANSSEN-CILAG for generous additional support. We thank
CSIC for a doctoral fellowship to A.C.
Synthesis of (+)-(1′R,2S,3S)-2-(1′-Hydroxybenzyl)-2-(p-tolyl-
sulfonyl)-3-vinyloxirane, 13b. From a solution of dienyl sulfoxide
6b9 (300 mg, 1.01 mmol) in C6H6 (5.0 mL) with VO(acac)2 (0.15
equiv) and t-BuOOH (5.0 equiv, 5.0-6.0 M in decane) according
to the general procedure (1 day) was obtained a 72:28 mixture of
13b and 14b. Chromatography (5-30% EtOAc-hexane, then
0-5% EtOAc-CH2Cl2) gave sulfonyl oxirane 13b (221 mg, 67%)
Supporting Information Available: Experimental procedures
and characterization for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO052244D
J. Org. Chem, Vol. 71, No. 4, 2006 1575