Nucleophilic epoxidation of α′-hydroxy dienyl sulfoxides

Article abstract of DOI:10.1021/jo0349173

A novel route to enantiopure densely functionalized epoxy sulfinyl tetrahydrofurans, based on the unexpected and highly stereoselective remote nucleophilic epoxidation of hydroxy 1-sulfinyl butadienes with t-BuOOK, followed by ring closure and subsequent

Full text of DOI:10.1021/jo0349173

Nu cleop h ilic Ep oxid a tion of r′-Hyd r oxy Dien yl Su lfoxid es
Roberto Ferna´ndez de la Pradilla,*,† Pilar Manzano,† Carlos Montero,† J ulia´n Priego,†
Mart´ın Mart´ınez-Ripoll,‡ and Luis A. Mart´ınez-Cruz‡
Instituto de Qu´ımica Orga´nica, CSIC, J uan de la Cierva, 3, 28006 Madrid, Spain, and Departamento de
Cristalografı´a, Instituto de Qu´ımica-Fı´sica Rocasolano, CSIC, Serrano 119, 28006 Madrid, Spain
iqofp19@iqog.csic.es
Received J une 27, 2003
A novel route to enantiopure densely functionalized epoxy sulfinyl tetrahydrofurans, based on the
unexpected and highly stereoselective remote nucleophilic epoxidation of hydroxy 1-sulfinyl
butadienes with t-BuOOK, followed by ring closure and subsequent epoxidation of the resulting
sulfinyl dihydrofurans, is described. Alternatively, the treatment of these dienes with m-CPBA
followed by acid-catalyzed cyclization gives rise to related sulfonyl dihydrofurans in high yields
but with low selectivity. The stereochemical outcome of the nucleophilic epoxidation of these
substrates has also been studied.
In tr od u ction
1), should produce oxiranes B, adequate precursors of
carbohydrates by simple manipulations.5 At this stage
we realized that the 1,4 conjugate addition pathway could
be operative to some extent,6 but we considered that it
would just result in diminished yields. On the other hand,
if this 1,4-pathway were selective, which was perceived
as unlikely, oxiranes C could be produced and this could
outline a simple entry to the tetrahydrofuran core, an
ubiquitous building block for bioactive products.7 In this
report we describe in full our studies on the development
of a novel strategy for the expedient preparation of highly
substituted tetrahydrofurans D from hydroxy sulfinyl
dienes A. This unexpected process takes place primarily
by an unusually selective remote nucleophilic epoxidation
of dienes A followed by ring closure of vinyl sulfinyl
The nucleophilic epoxidation of simple vinyl sulfoxides
is a general and efficient route to enantiopure sulfinyl
and sulfonyl oxiranes,1 versatile synthetic intermediates.2
For a number of years we have been engaged in an in-
depth study of the scope of this unique process. Our
initial survey of the epoxidation of vinyl sulfoxides
bearing additional oxygenated substituents at allylic
positions indicated that the selectivity of the process was
primarily controlled by the chiral sulfur center.3 Subse-
quent detailed studies have revealed that this control by
sulfur was not always operative,4 but at the time, and
seeking to apply our methodology to the preparation of
carbohydrate fragments, we considered that the nucleo-
philic epoxidation of hydroxy dienyl sulfoxides, A (Scheme
† Instituto de Qu´ımica Orga´nica.
(5) 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. We subsequently developed an alternative route to vinyl
oxiranes related to B; see: Ferna´ndez de la Pradilla, R.; Me´ndez, P.;
Priego, J .; Viso, A. J . Chem. Soc., Perkin Trans. 1 1999, 1247-1249.
(6) For 1,4-additions of lithiated protected cyanohydrins to a dienyl
sulfoxide, see: (a) Guittet, E.; J ulia, S. Tetrahedron Lett. 1978, 37,
1155-1158. (b) Guittet, E.; J ulia, S. Synth. Commun. 1981, 11, 697-
708. (c) Guittet, E.; J ulia, S. Synth. Commun. 1981, 11, 709-722.
(7) For reviews on the synthesis of tetrahydrofurans, 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. For selected
references about bioactive tetrahydrofurans see: (d) Westley, J . W.
Polyether Antibiotics: Naturally Occurring Acid Ionophores; Marcel
Dekker: New York, 1982; Vols. 1 and 2. (e) Acetogenins: Alali, F. Q.;
Liu, X.-X.; McLaughlin, J . L. J . Nat. Prod. 1999, 62, 504-540. (f) Zafra-
Polo, M. C.; Figade`re, B.; Gallardo, T.; Tormo, J . D.; Cortes, D.
Phytochemistry 1998, 48, 1087-1117. (g) C-Nucleosides: Du, Y. G.;
Linhardt, R. J .; Vlahor, I. R. Tetrahedron 1998, 54, 9913-9959. (h)
J aramillo, C.; Knapp, S. Synthesis 1994, 1-20. For recent related
references, see: (i) J iang, L.; Burke, S. D. Org. Lett. 2002, 4, 3411-
3414. (j) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461-464.
(k) Smitrovich, J . H.; Woerpel, K. A. Synthesis 2002, 2778-2785. (l)
Choi, H.; Nakajima, K.; Demeke, D.; Kang, F.-A.; J un, H.-S.; Wan, Z.-
K.; Kishi, Y. Org. Lett. 2002, 4, 4435-4438. (m) J eong, E. J .; Kang, E.
J .; Sung, L. T.; Hong, S. K.; Lee, E. J . Am. Chem. Soc. 2002, 124,
14655-14662. (n) Peng, Z.-H.; Woerpel, K. A. J . Am. Chem. Soc. 2003,
125, 6018-6019.
‡ Instituto de Qu´ımica-F´ısica Rocasolano.
(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) 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.
(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.
(3) Ferna´ndez de la Pradilla, R.; Manzano, P.; Priego, J .; Viso, A.;
Mart´ınez-Ripoll, M.; Rodr´ıguez, A. Tetrahedron Lett. 1996, 37, 6793-
6796.
(4) 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.
10.1021/jo0349173 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/06/2003
J . Org. Chem. 2003, 68, 7755-7767
7755

Ferna´ndez de la Pradilla et al.
SCHEME 1
SCHEME 3
SCHEME 4
SCHEME 2
below) into the “reactive” diastereomers 4 was explored.
Initially we intended to carry out a nucleophilic substitu-
tion with KO2 on the mesylate of 3a (Scheme 4);11
however, the use of MsCl/Et3N resulted in SN2′ displace-
ment by chloride to produce a conjugated trienyl chloride
related to 7. The use of Ms2O with a number of different
bases (Et3N, pyr, DBU) gave exclusively the mesylate of
trienol 7, presumably due to conjugate addition of meth-
anesulfonate anion to the mesylate of 3a . We then turned
our attention to the Mitsunobu protocol using p-NO2C6H4-
CO2H,12 followed by deprotection of the p-nitrobenzoate.
Under these conditions, (Scheme 4) still a substantial
oxiranes C, and a second nucleophilic epoxidation of the
resulting sulfinyl dihydrofurans in a single synthetic
operation.
P r ep a r a tion of Sta r tin g Ma ter ia ls
(9) Lithiation of Z vinyl sulfoxides with organolithium reagents and
LDA yields E lithio derivatives. Substantial racemization was reported
for the lithiation of Z vinyl sulfoxides with organolithium reagents,
see: (a) Posner, G. H. In Asymmetric Reactions and Processes in
Chemistry; Eliel, E. L., Otsuka, S., Eds.; ACS Symp. Ser. No. 185;
American Chemical Society: Washington, DC, 1982; p 142. (b) Fawcett,
J .; House, S.; J enkins, P. R.; Lawrence, N. J .; Russell, D. R. J . Chem.
Soc., Perkin Trans. 1 1993, 67-73. We have measured the optical
rotations of a variety of E vinyl and dienyl sulfoxides arising from the
lithiation of Z isomers (LDA, -78 °C) and we did not find significant
differences with the rotations of the pure E isomers derived from
Horner-Emmons procedures. For a recent report on the intramolecular
alkylation of R-sulfinyl vinyl carbanions, see: (c) Maezaki, N.; Izumi,
M.; Yuyama, S.; Sawamoto, H.; Iwata, C.; Tanaka, T. Tetrahedron
2000, 56, 7927-7945.
(10) All new products have been fully characterized. See the
Supporting Information. The stereochemical assignment for dienols 3
and 4 is based on careful comparison of their 1H and 13C NMR data,
as well as chromatographic behavior with the data of a series of related
compounds, one of which was characterized by X-ray crystallography,
see: Marino, J . P.; Viso, A.; Lee, J .-D.; Ferna´ndez de la Pradilla, R.;
Ferna´ndez, P.; Rubio, M. B. J . Org. Chem. 1997, 62, 645-653.
(11) Corey, E. J .; Nicolau, K. C.; Shibashaki, M.; Machida, Y.; Shiner,
C. S. Tetrahedron Lett. 1975, 3183-3186.
Scheme 2 shows the preparation of a number of dienols
3a -g and 4a -g, obtained by lithiation of the mixture of
dienes 1a -2a , available in one step by the method of
Craig,8 and reaction with a variety of aldehydes followed
by chromatographic separation.9,10 To explore the behav-
ior of some dienyl sulfones in this process, dienes 4a and
4e were oxidized smoothly under standard conditions
(MMPP, Scheme 3). Pyridine-containing substrate 4g
required carefully controlled reaction conditions to pre-
vent substantial overoxidation to the corresponding N-
oxide from taking place (see Supporting Information for
details).
To enhance the efficiency of this methodology, the
transformation of the “unreactive” diastereomers 3 (see
(8) Craig, D.; Daniels, K.; McKenzie, A. R. Tetrahedron 1993, 49,
11263-11304.
7756 J . Org. Chem., Vol. 68, No. 20, 2003

Epoxidation of R′-Hydroxy Dienyl Sulfoxides
TABLE 1. Nu cleop h ilic Ep oxid a tion of Sim p le Su lfin yl Dien es
entry
substrate
conditions
8a
9a
10a
11a
yield,b %
1
2
1a
2a
2a
2a
2a
2b
2c
2 equiv of KOO-t-Bu, 4 °C, 22 h
2 equiv of NaOO-t-Bu, 0 °C, 4 h
decomp
NR
10
36
50
3c
4d
5e
6f
7
2 equiv of KOO-t-Bu, 0 °C, 10 min
1 equiv of KOO-t-Bu, -78 to 0 °C, 35 min
2 equiv of KOO-t-Bu, -20 to 0 °C, 1 h
2 equiv of KOO-t-Bu, -20 to 0 °C, 135 min
3 equiv of KOO-t-Bu, -20 to 0 °C, 90 min
8a (64)
8a (9)
8a (60)
9a (28)
9a (76)
9a (33)
9b (70)
10a (8)
10a (15)
10a (7)
traces
11b (30)
ND
56
8c
a
b
Stereochemical assignments are tentative. Yields of pure products after column chromatography. c Reaction proceeded to ca. 30%
conversion. Reaction proceeded to ca. 71% conversion. e Reaction proceeded to ca. 91% conversion. f Reaction proceeded to ca. 51%
d
conversion.
amount of trienol 7 was obtained. After some optimiza-
tion, dienol 3e gave more satisfactory results affording
an 86:14 mixture of 4e and 3e in good yield.
Syn th esis of Tetr a h yd r ofu r a n s fr om Hyd r oxy
Su lfin yl a n d Su lfon yl Dien es
The initial stage of our investigation was carried out
on dienol 3a that was found to be very unreactive to the
standard conditions, and under forcing conditions led to
intractable mixtures of products that were not investi-
gated in detail. In sharp contrast, diastereomeric dienol
4a reacted with KOO-t-Bu to afford a low yield of a
sulfinyl tetrahydrofuran. Scheme 5 gathers the majority
of intermediates and products that we considered reason-
able for this complex tandem process. We believed the
process to commence by a remote nucleophilic epoxidation
affording monoepoxides 12 and 13. At this point two
distinct pathways were considered reasonable. Pathway
A (Scheme 5) entails a 5-exo-trigonal cyclization leading
to sulfinyl dihydrofurans 16 or 17 respectively followed
by a second nucleophilic epoxidation to sulfinyl tetrahy-
drofurans 18-21 which under the reaction conditions
could undergo a facile oxidation at sulfur to some extent
to afford sulfonyl tetrahydrofurans 22-25. On the other
hand, pathway B entails a second epoxidation on mo-
noepoxides 12 and 13 to produce bisepoxides 14 and 15
that would undergo a base-promoted 5-exo-trigonal cy-
clization to sulfinyl tetrahydrofurans 18-21.14 It should
be noted that both pathways could be operative simul-
taneously leading to diastereomeric products due to the
presumably different stereochemical outcome of the
second nucleophilic epoxidation that takes place on
different substrates.
Ep oxid a tion of Sim p le Su lfin yl Dien es
Having established the viability and reproducibility of
the first few examples of this methodology,13 which, for
clarity, will be discussed below, we chose to explore
briefly the reactivity of simple sulfinyl dienes under these
conditions to establish if these simpler substrates could
also undergo a stereoselective remote epoxidation and the
results obtained are gathered in Table 1. The simplest
1E diene, 1a , gave no reaction at short times or under
more forcing conditions delivered a complex reaction
mixture with substantial decomposition (Table 1, entry
1). In contrast, 1Z isomer 2a rapidly gave a low yield of
a mixture of 1,2 monoepoxide 8a and bisepoxides 9a and
10a , along with recovered starting material (entry 3).
Entries 4 and 5 indicate that the outcome of the reaction
is highly dependent on the temperature with low tem-
peratures favoring initial remote epoxidation followed by
a second 1,2 epoxidation. It should be pointed out that
all stereochemical assignments for these products (8-
11) are tentative, particularly those of the bisepoxides.
In view of our lack of success with the 1E isomer 1a , the
rest of this exploratory study was carried out on the Z
isomers. Thus, quite to our surprise, diene 2b, bearing a
substituent at C-4, gave a 70:30 mixture of sulfinyl and
sulfonyl bisepoxides 9b and 11b both as single isomers.
Finally, diene 2c, bearing a substituent at C-3, gave
exclusively monoepoxide 8c derived from 1,2-attack. The
results obtained in this quick survey indicate that, in
some cases, simple 1Z sulfinyl dienes can undergo a
selective remote epoxidation, followed by a second 1,2
epoxidation under the reaction conditions.
With these considerations in mind, we set out on a
detailed study of this complex and unexpected process
with the goals of trying to isolate reaction intermediates
to shed some light on the reaction pathway while, if
possible, improving the yields of the process and testing
the scope of the methodology. The results obtained are
shown in Table 2. It should be pointed out that in many
cases the substantial complexity of the process has
rendered the ratios reported below just approximate; in
(12) (a) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017-
3020. For reviews, see: (b) Hughes, D. L. Org. React. 1992, 42, 335-
668. (c) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127-164.
(13) For a preliminary communication, see: Ferna´ndez de la Pra-
dilla, R.; Montero, C.; Priego, J .; Mart´ınez-Cruz, L. A. J . Org. Chem.
1998, 63, 9612-9613.
(14) Baldwin, J . E. Chem. Commun. 1976, 734-736.
J . Org. Chem, Vol. 68, No. 20, 2003 7757

Ferna´ndez de la Pradilla et al.
SCHEME 5
addition, this methodology is very dependent on the
precise reaction conditions used, including reaction tem-
perature, stoichiometry, and reaction time.
2, entry 8). The behavior of substrates bearing aliphatic
substituents of different size (4c, R3 ) Et and 4d , R3 )
i-Pr) was then examined and the results obtained are
gathered in entries 9-13. In most cases the overall yields
obtained were higher (44-59%), important amounts of
sulfinyl dihydrofurans were isolated, and the overall
selectivity of the process was substantially diminished
for the second epoxidation of the dihydrofurans, in the
case of 4c (18c:19c, ca. 70:30) and also for the remote
epoxidation in the case of 4d (16d :17d , 77:23).
In contrast with the results above, the reaction of Ph-
substituted 4e gave diminished yields and a substantial
amount of a bisepoxide (ca. 25%), presumably 14e, when
the process was started at -20 °C (Table 2, entry 14).
Furthermore, a substantial reduction of both cis:trans
and R:â selectivities was also found. Carrying out the
process at 0 °C gave an improvement in yield but with
comparable selectivities (entry 15). Dienyl sulfone 6e was
also tested and a rather complex mixture of products was
obtained with an estimated 87:13, 2,5-cis:2,5-trans se-
lectivity (entry 16). This result is comparable to that
shown in entry 17 that gathers the results obtained by
sequential epoxidation of sulfinyl dienol 4e followed by
oxidation of the crude with m-CPBA. It should be
mentioned that the selectivity found for the major 2,5-
cis products from the sulfoxide (entry 17; 22e:23e, 91:9)
is slightly better than that obtained from the dienyl
sulfone (entry 16; 22e:23e, 79:21).
At short reaction times (10 min), a small amount of
monoepoxide 12a (7%) was isolated from the reaction
between 4a and KOO-t-Bu (Table 2, entry 1). Similarly,
the use of 0.85 equiv of reagent gave a small amount (ca.
10%) of sulfinyl dihydrofuran 16a (entry 2) that was
epoxidized under standard conditions to produce an 85:
15 mixture of 18a and 22a (entry 3). These findings
support pathway A (Scheme 5) as a reasonable sequence
of events for these processes. After considerable experi-
mentation, it was determined that for 4a optimal results
could be obtained by slowly adding a THF solution of the
substrate to a cold (-20 °C) THF solution of KOO-t-Bu,
allowing the reaction temperature to warm to 0 °C
rapidly, and then quenching after a relatively short time
at 0 °C. Thus, 4a gave an 83:17 separable mixture of
sulfoxide 18a and sulfones 22a (90:10 mixture) in 48%
yield (entry 4). The use of an excess of reagent and longer
reaction time (entry 5) resulted in much more overoxi-
dation to sulfones 22a and in a much lower yield (18%).
Finally, the possibility of using hydroxy sulfonyl dienes
as substrates for this process was explored, seeking to
establish the viability of the protocol and also the
stereochemical implications of the allylic center as the
sole element of stereocontrol, and the results obtained
are shown in entries 6 and 7. Thus it appears that the
process is viable even with the milder reagent NaOO-t-
Bu, but in lower yield and with substantially diminished
selectivity to produce the major isomer 22a along with
two minor isomers of unknown precise stereochemistry
in 62:29:9 ratio.
This chemistry was also extended to heteroaromatic
substrate 4f, bearing a 3-pyridyl moiety, and to evaluate
the stereodirecting capabilities of the allylic center, to
dienyl sulfone 6f, and the results obtained are shown in
Table 2, entries 18 and 19. The results obtained parallel
those found for 4e and 6e (R3 ) Ph), except for the fact
that bisepoxides were not isolated in this case.
1-Propenyl-substituted substrate 4b gave a comparable
outcome to 4a with slightly diminished selectivity (Table
7758 J . Org. Chem., Vol. 68, No. 20, 2003

Epoxidation of R′-Hydroxy Dienyl Sulfoxides
TABLE 2. Syn th esis of Tetr a h yd r ofu r a n s fr om Hyd r oxy Su lfin yl Dien es (4) a n d Hyd r oxy Su lfon yl Dien es (6)
entry
1
substrate
conditions
12, 13
16, 17a
18-21a
22-25a
yield,b %
4a
2 equiv of KOO-t-Bu,
-20 to 0 °C, 10 min
0.85 equiv of KOO-t-Bu,
-78 to 4 °C, 18 h
4.0 equiv of KOO-t-Bu,
-20 to 0 °C, 1 h
2.0 equiv of KOO-t-Bu,
-20 to 0 °C, 40 min
3.0 equiv of KOO-t-Bu,
-20 to 0 °C, 4 h
2.0 equiv of KOO-t-Bu,
-20 to 0 °C, 10 min
4.0 equiv of NaOO-t-Bu,
0 °C to rt, 8 h
12a
ND
ND
ND
7
2
3
4a
16a
4a
4a
6a
6a
4b
4c
4c
4c
4d
4d
4e
4e
6e
16a (38)
18a (54)
18a (85)
18a (83)
18a (18)
22a (8)
10c
47
22a (15)
4
traces
22a (17)
[90:10]
22a (82)
[90:10]
22a -25a
[62:29:9]
22a -25a
[62:29:9]
22b (10)
48d
18d
29d
NDd
36d
50
5
6
7
8
2.0 equiv of KOO-t-Bu,
0 °C, 30 min
18b (90)
[90:10]
18c:19c (47)
[73:27]
18c:19c (19)
[70:30]
18c:19c (17)
9
1.5 equiv of KOO-t-Bu,
-25 to 0 °C, 105 min
1.5 equiv of KOO-t-Bu,
-25 to 0 °C, 1 h
3.0 equiv of KOO-t-Bu,
-25 to 0 °C, 1 h
1.6 equiv of KOO-t-Bu,
-30 to -5 °C, 25 min
1.5 equiv of KOO-t-Bu,
-30 to -5 °C, 75 min
1.8 equiv of KOO-t-Bu,
-20 to 0 °C, 50 min
1.8 equiv of KOO-t-Bu,
0 °C, 50 min
16c (27)
16c (37)
22c:23c (26)
[70:30]
22c:23c (25)
[70:30]
22c:23c (83)
[77:23]
22d -25d (25)
[53:13:13:11]
22d -25d (33)
10
11
12
13
14
15
16
44e
50
16d :17d (35)
[77:23]
16d :17d (38)
18d -20d (40)
[73:12:15]
18d -20d (29)
59
59f
33g
42
16e:17e (12)
[80:20]
18e-20e (77)
[77:18:5]
18e-20e (87)
[74:14:12]
22e-24e (11)
[65:35]
22e-24e (13)
[62:38]
22e:23e/24e:25e
(87/13)
2.0 equiv of KOO-t-Bu,
-10 to 0 °C, 30 min
ND
[79:21/85:15]
22e:23e/24e:25e
(86/14)
17
4e
(1) 1.8 equiv of KOO-t-Bu,
0 °C, 70 min;
30
(2) mCPBA, CH2Cl2
2.0 equiv of KOO-t-Bu,
-20 to 0 °C, 75 min
2.0 equiv of KOO-t-Bu,
-30 to -5 °C, 1.5 h
[91:9/76:24]
22f-25f (4)
[68:32]
22f:23f/24f:25f
(85/15)
[87:13/73:27]
22g-25g (20)
18
19
4f
6f
16f:17f (20)
[90:10]
18f-20f (76)
39
28
[95:5:5]
20
21
22
23
24
25
4g
4g
4g
4g
4 g
5
2.0 equiv of KOO-t-Bu,
-40 to 0 °C, 40 min
2.0 equiv of KOO-t-Bu,
0 °C, 70 min
3.0 equiv of KOO-t-Bu, CH2Cl2,
0 °C, 70 min
2.0 equiv of KOO-t-Bu, CH2Cl2,
0 °C, 40 min
3.0 equiv of KOO-t-Bu, Tol,
0 °C, 24 h
18g-21g (47)
36g
41
16g:17g (9)
[89:11]
16g-17g (40)
[90:10]
16g:17g (47)
18g-20g (78)
[62:21:17]
18g-20g (50)
[75:15:10]
22g-25g (13)
[61:21:11:7]
22g-25g (10)
[52:32:10:6]
22g-25g (8)
36
18g-20g (45)
67h
NDi
61j
16g:17g (67)
18g-20g (20)
22g-25g (13)
1.8 equiv of KOO-t-Bu,
4 °C, 3.5 days
16h :17h (20)
[75:25]
18h -21h (50)
[48:0:31:21]
22h :23h (30)
[77:23]
a
Relative amounts of products are shown in parentheses and the diastereomeric ratios for each type of product are shown in brackets;
in some cases these ratios were not measured. Combined yields of pure products after column chromatography. c This yield refers only
b
to sulfinyl dihydrofuran 16a . The stereochemistry of the minor products was not established. e Reaction carried out on a 4 mmol scale
d
with reagent “aged” for 90 min; a sulfenate byproduct was obtained (see Supporting Information). f Reaction carried out on a 4 mmol
g
h
i
scale. Acyclic bis-epoxides 14 were also isolated (see Supporting Information). Yield includes 20% recovered starting material. About
40% ratio of starting material was present in the crude mixture (1H NMR); the yield was not determined. Yield includes 40% recovered
j
starting material.
Entries 20-24 gather our efforts on substrate 4g (R3
) p-F-Ph) that gave comparable results to those found
for 4e (R3 ) Ph), including the production in ca. 23%
yield of bisepoxide 14g when the reaction was started at
J . Org. Chem, Vol. 68, No. 20, 2003 7759

Ferna´ndez de la Pradilla et al.
TABLE 3. Oxid a tion -Ep oxid a tion of Hyd r oxy Su lfin yl Dien es
entry substrate
conditions
6:26,27:28,29 monoepoxides 26:27 dihydrofurans 28:29 yield,a
%
1
2
3
4
5
6
7
3e
3e
3e
3c,4c
3d ,4d
3g,4g
3g,4g
CH2Cl2, 4 days
Et2O, 5 days
Tol, 3.5 days
Tol, 20 h
Tol, 38 h
Tol, 3 days
0:81:19
0:50:20
0:80:20
9:91:0
0:70:30
0:83:17
0:0:0
26e (57):27e (43)
26e (50):27e (50)
26e (61):27e (39)
26c (62):27c (38)
26d (58):27d (42)
26g (59):27g (41)
0:0
28e (57):29e (43)
28e (50):29e (50)
28e (61):29e (39)
0:0
28d (75):29d (25)
28g (75):29g (25)
28g (60):29g (40)
73
76
76
85
84
94
84
5 equiv of mCPBA, Tol, 3 days;
then 0.2 equiv of CSA
8
9
10
11
12
13
6g
6g
6g
3g
3g
5
oxone, MeOH, H2O, rt, 22 h
acetone, oxone, NaHCO3, H2O, rt, 46 h
DMDO, CH2Cl2, 0 °C, 4 h
CH3CN, H2O2, NaHCO3, MeOH, rt, 6 days
PhCN, H2O2, NaHCO3, MeOH, rt, 4 days
mCPBA, Tol, rt, 2 days
80:0:20
80:10:10
9:77:14
30:0:70
20:0:80
0:0:0
0:0
28g (60):29g (40)
28g (45):29g (55)
28g (50):29g (50)
28g (70):29g (30)
28g (70):29g (30)
30
18
ND
74
61
ND
85
26g (45):27g (55)
26g (50):27g (50)
0:0
0:0
0:0
a
Combined yields of pure products after column chromatography, including starting material.
-40 °C (entry 20) and the production of a 9:78:13 mixture
of dihydrofurans, sulfinyl, and sulfonyl tetrahydrofurans
(entry 21). In an effort to understand better this process,
particularly the cause of the lower yields obtained for
substrates bearing R3 ) Aryl, alkenyl, relative to those
bearing alkyl groups, and guided by finding variable
amounts of p-fluorobenzaldehyde in the crude reaction
mixtures, we examined the stability of dienol 4g to
KO-t-Bu (THF, 0 °C, 2 h); this experiment resulted in
substantial fragmentation with recovery of just 62% of
4g and the corresponding amounts of aldehyde and
sulfinyl diene 1a . Thus it appears that another competing
reaction pathway, this undesired fragmentation provoked
by the KO-t-Bu released as the epoxidation takes place,
or even perhaps by KOO-t-Bu, is also operative in these
processes.
In view of these findings we surveyed the use of other
solvents to try to improve the overall efficiency of the
process. Toluene gave rise to a very slow reaction (entry
24) and CH2Cl2 gave slightly better results by enhancing
the rate of cyclization of monoepoxide 12, which, in
contrast with the standard conditions, could not be
detected by TLC, but diminishing the rate of the second
epoxidation, affording important amounts of dihydro-
furans (entry 22). Entry 23 shows that a slightly better
overall yield can be obtained by performing the reaction
in CH2Cl2 at short reaction times to produce a mixture
of products in 66% yield, including 20% recovered start-
ing material. Finally, the behavior of substrate 5, bearing
gem-dimethyl substituents, was examined and a rather
complex mixture of products was obtained in low yield
and with low conversion (entry 25).
P r ep a r a tion a n d Nu cleop h ilic Ep oxid a tion of
Su lfon yl Dih yd r ofu r a n s
At this stage we decided to explore an alternative route
to 2,5-cis and 2,5-trans sulfonyl dihydrofurans related to
16 and 17 (Scheme 5). We were attracted by the synthetic
potential of these intermediates that have scarcely been
documented in the literature.15 More relevant to this
project, we believed that a careful study of the nucleo-
philic epoxidation of these substrates could allow for firm
structural assignments for our sulfinyl and sulfonyl
tetrahydrofurans. On the basis of literature precedents,16
we envisioned the simplest route to achieve this goal to
be the simultaneous oxidation and epoxidation with
m-CPBA, followed by acid- or base-catalyzed cyclization
of the resulting vinyl oxiranes.
Table 3 gathers our results on this oxidation-epoxi-
dation protocol. Treatment of hydroxy sulfinyl diene 3e
with m-CPBA in CH2Cl2 resulted in a fast oxidation to
the dienyl sulfone followed by a slow epoxidation at the
distal double bond to produce a separable mixture of
monoepoxides 26e and 27e, along with significant amounts
of dihydrofurans 28e and 29e in good overall yield (Table
3, entry 1). The influence of the solvent on the rate and
(15) Craig, D.; Ikin, N. J .; Mathews, N.; Smith, A. M. Tetrahedron
1999, 55, 13471-13494.
(16) (a) For the use of m-CPBA with high selectivity within this
context, see: Iqbal, J .; Pandey, A.; Chauban, B. P. S. Tetrahedron 1991,
47, 4143-4154. (b) For a related report with MMPP followed by CSA,
see: Kang, S. H. Tetrahedron Lett. 1989, 30, 5915-5918. See also: (c)
Urones, J . G.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; San Feliciano,
S. G.; Coca, R.; D´ıez, D. Synlett 1998 1364-1365. (d) D´ıez, D.; Beneitez,
M. T.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Urones, J . G.
Tetrahedron: Asymmetry 2002, 13, 639-646
7760 J . Org. Chem., Vol. 68, No. 20, 2003

Epoxidation of R′-Hydroxy Dienyl Sulfoxides
TABLE 4. Acid -Ca ta lyzed P r ep a r a tion of Su lfon yl
Dih yd r ofu r a n s fr om Su lfon yl Dien e Mon oep oxid es
selectivity of the process was then briefly examined
(entries 2 and 3), with toluene providing a slightly better
selectivity and faster rate of reaction. In view of the poor
selectivity found we chose to carry out this part of the
study using racemic materials, therefore it was appropri-
ate in some cases to use diastereomeric mixtures of
hydroxy dienes 3 and 4 that would produce racemic
sulfones 6, eventually leading to racemic dihydrofurans.
Thus, entries 4-6 show the results obtained for the other
substrates of this study that paralleled those above
except that for R3 ) Et, i-Pr the epoxidations were a little
faster. It was also possible to carry out a one-pot protocol
by adding catalytic CSA to the crude epoxidation mixture
affording sulfonyl dihydrofurans 28g and 29g that,
unlike for most of the previous examples, were separated
readily.
A few simple alternative epoxidizing conditions (entries
8-12) were also surveyed in an attempt to improve the
selectivity of the process. Oxone in MeOH gave a similar
selectivity but in a slow reaction (entry 8). Oxone in
acetone also gave a poorly selective process with low
conversion (entry 9). The use of freshly prepared dimethyl
dioxirane in CH2Cl2 gave a rapid reaction, unfortunately
devoid of selectivity (entry 10). Entries 11 and 12 gather
the results obtained with peroxyminic acids,17 generated
in situ from H2O2 and nitriles, that gave a slow reaction,
with slightly better selectivity (70:30) and a small (entry
11, ca. 10%) or significant (entry 12, ca. 50%) amount of
epoxy sulfonyl tetrahydrofurans. Finally, the treatment
of substrate 5, bearing a gem-dimethyl moiety, with
m-CPBA smoothly gave sulfonyl dihydrofuran 30 in
excellent yield (entry 13).
The cyclization of diastereomeric vinyl oxiranes 26 and
27 was then examined, initially, under basic conditions.
Thus t-BuOK (THF, rt, 8 h) led to recovered starting
material and NaH (0 °C to room temperature, 5 h)
afforded small amounts of dihydrofurans and a complex
mixture of products. Alternatively, the use of catalytic
CSA (0.2 equiv, CH2Cl2, rt) gave excellent yields of
sulfonyl dihydrofurans 28 and 29 that are gathered in
Table 4.18
Table 5 shows our efforts on the epoxidation of 2,5-cis
sulfonyl dihydrofurans 28. Entries 1-3 show the results
obtained for model substrate 28e with different meta-
lated peroxides in THF for which the best selectivity was
obtained with LiOO-t-Bu (91:9, entry 1). Under identical
conditions, ethyl-substituted substrate 28c gave a sub-
stantially diminished selectivity (71:29, entry 4), appar-
ently independent in this case of the counterion (entry
5, 72:28). Finally, more sterically demanding substrates
28d and 28g gave adequate results with LiOO-t-Bu
(entries 6 and 7). In some cases (entries 1 and 6), small
amounts of sulfonyl furans 31 were also isolated; the
reaction pathway that leads to these furans has not been
investigated.
entry
substrate
R3
Ph
product
yielda
1
2
3
4
5
6
7
8
26e
26c
26d
26g
27e
27c
27d
27g
28e
28c
28d
28g
29e
29c
29d
29g
99%
98%
97%
99%
96%
96%
99%
99%
Et
i-Pr
p-F-Ph
Ph
Et
i-Pr
p-F-Ph
a
Yields of pure products after column chromatography.
epoxidation anti to the hydroxymethyl moiety were
obtained for the other substrates tested (entries 4-6).
Again, small amounts of sulfonyl furans 31 were also
isolated. Finally Scheme 6 shows that dimethyl-substi-
tuted dihydrofuran 30 also gave rise to the corresponding
tetrahydrofurans 22h and 23h with moderate selectivity
under standard conditions.
Ch em ica l Cor r ela tion s
The structures of these sulfinyl and sulfonyl oxiranes
were assigned by spectroscopic methods (1H and 13C NMR
and NOE experiments in some cases). However, a defini-
tive structural assignment was obtained by an X-ray
diffraction analysis of p-nitrobenzoate 32, prepared from
sulfinyl tetrahydrofuran 18a under standard conditions
(Scheme 7).19 In addition, a number of sulfinyl tetrahy-
drofurans and dihydrofurans were oxidized smoothly
under standard conditions (MMPP or m-CPBA) to pro-
duce the corresponding sulfones and the results obtained
are gathered in Schemes 7 and 8.
Resu lts a n d Discu ssion
There are several stereochemical issues to address
when trying to rationalize this complex process and our
thoughts, assuming an early transition state for each
transformation involved, are given below. The first aspect
is the lack of reactivity of diastereomers 3, relative to
diastereomers 4. This may be understood by admitting
that the intramolecular hydrogen bond plays an impor-
tant role for the less polar diastereomer 3 than for the
more polar diastereomer 4. In this manner, chelated
In contrast with the results above, the epoxidations of
2,5-trans sulfonyl dihydrofurans 29e were significantly
more selective when KOO-t-Bu was used (Table 6, entry
3) and in this case comparable selectivities in favor of
(17) (a) Payne, G. B. Tetrahedron 1962, 18, 763-765. (b) Bachmann,
C.; Gesson, J .-P.; Renoux, B.; Tranoy, I. Tetrahedron Lett. 1998, 39,
379-382.
(18) Nicolau, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K.
J . Am. Chem. Soc. 1989, 111, 5330-5334.
(19) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre (CCDC 213296,
refcode: DADNUR). The coordinates can be obtained, on request, from
the Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ. UK.
J . Org. Chem, Vol. 68, No. 20, 2003 7761

Ferna´ndez de la Pradilla et al.
TABLE 5. Nu cleop h ilic Ep oxid a tion of 2,5-Cis Su lfon yl Dih yd r ofu r a n s
entry
substrate
R3
Ph
Ph
Ph
Et
Et
i-Pr
p-F-Ph
M
conditions
22
23
31
yield,a
%
1
2
3
4
5
6
7
28e
28e
28e
28c
28c
28d
28g
Li
Na
K
Li
K
-65 to 0 °C, 6 h
0 °C, 25 min
22e (91)
22e (59)
22e (59)
22c (71)
22c (72)
22d (83)
22g (87)
23e (9)
31e (5%)
70
59
78
72
88
78
82
23e (41)
23e (41)
23c (29)
23c (28)
23d (17)
23g (13)
-40 to -15 °C, 50 min
-20 to 0 °C, 24 h
-40 to 0 °C, 45 min
-20 to 0 °C, 6 h
0 °C, 2 h 30 min
Li
Li
31d (8%)
a
Combined yields of pure products after column chromatography.
TABLE 6. Nu cleop h ilic Ep oxid a tion of 2,5-Tr a n s Su lfon yl Dih yd r ofu r a n s
entry
substrate
R3
Ph
Ph
Ph
Et
i-Pr
p-F-Ph
M
conditions
24
25
31
yield,a
%
1
2
3
4
5
6
29e
29e
29e
29c
29d
29g
Li
Na
K
K
K
-65 to 0 °C, 21 h
0 °C, 20 min
-40 to -30 °C, 20 min
-60 to -20 °C, 130 min
-60 to -20 °C, 105 min
-50 to -15 °C, 25 min
24e (24)
24e (23)
24e (8)
24c (5)
24d (4)
24g (7)
25e (76)
25e (77)
25e (92)
25c (95)
25d (96)
25g (93)
87
69
84
56
73
82
31c (4%)
31d (8%)
K
a
Combined yields of pure products after column chromatography.
SCHEME 6
base-induced cyclization follows to produce 2,5-cis dihy-
drofurans 16; however, for R3 ) Ph, p-F-Ph, at low
temperature (-20 °C) this cyclization is relatively slow
and 12 may undergo a second nucleophilic epoxidation
to generate bisepoxides.
The case of the simple Z sulfinyl dienes discussed in
Table 1 can also be tentatively rationalized by considering
reactive conformer G (Scheme 10) with an s-cis arrange-
ment of the lone pair on sulfur and the alkene,20 and
coordination of the metalated peroxide to the sulfinyl
oxygen followed by oxirane formation in a 1,2-fashion to
yield 8 that cannot undergo a second epoxidation or in a
1,4-fashion to produce a transient monoepoxide that
undergoes a second epoxidation to produce bisepoxides
9. It should be mentioned that this part of the study was
only explored briefly and therefore the stereochemical
assignments are just tentative. In addition these pro-
cesses were found to be very substrate and temperature
dependent.
conformer A (Scheme 9), which places R3 and the bulky
p-Tolyl group in an equatorial arrangement, would be
more favorable for diastereomer 3 than the related
conformer C for diastereomer 4. This would disfavor
coordination between the hydroxyl group and the meta-
lated peroxide that we believe to be the main factor in
promoting and controlling the remote nucleophilic ep-
oxidation and thus other reaction pathways become
competitive.
The stereochemical outcome of the remote nucleophilic
epoxidation may be rationalized by considering a hy-
droxyl-directed process on reactive conformers E and F
(Scheme 10); the relative contribution of these conformers
would depend on a rather subtle balance of allylic strains.
It appears that for relatively small R3 groups, conformer
E is operative with nucleophilic remote conjugate addi-
tion of the peroxide anion to the R face of the molecule
followed by a rapid ring closure that retains the facial
and stereochemical integrity of the molecule to produce
predominantly vinyl oxirane 12. In most cases, a rapid
The selectivity of the epoxidations of 2,5-cis sulfonyl
dihydrofurans, 28, is quite substrate and metal depend-
ent with best results obtained for LiOO-t-Bu presumably
by R-attack, opposite to the hydroxymethyl substituent
(20) It should be noted that, for a simple Z-propenyl sulfoxide, the
energy difference between the more stable conformers (s-cis, CdC/Sd
O and s-cis, CdC/S-:) has been evaluated as just -0.4 kcal mol-1
.
See: Tietze, L. F.; Schuffenhauer, A.; Schreiner, P. R. J . Am. Chem.
Soc. 1998, 120, 7952-7958.
7762 J . Org. Chem., Vol. 68, No. 20, 2003

Epoxidation of R′-Hydroxy Dienyl Sulfoxides
SCHEME 7
SCHEME 8
SCHEME 9
on reactive conformer H (Scheme 11). In contrast, the
2,5-trans isomers, 29, give better results with KOO-t-
Bu and are not as substrate dependent, presumably by
â-attack on reactive conformer J , again opposite to the
hydroxymethyl substituent.21 With regard to the sulfinyl
oxiranes, the chiral sulfur center exerts in some cases a
reinforcing effect for the 2,5-cis isomers 16,22 enhancing
the low R-selectivity found for the related sulfones with
KOO-t-Bu. We believe that conformer L could be opera-
tive with perhaps some assistance by coordination of the
sulfinyl oxygen with the metalated peroxide. Thus, for
R3 ) Ph, the R:â selectivity goes from 59:41 for sulfonyl
dihydrofuran 28e to 91:9 estimated for epoxidation
followed by oxidation with m-CPBA of sulfinyl diene 4e.
Likewise, the minor 2,5-trans sulfinyl dihydrofurans 15
seem to also undergo a predominantly R-attack, syn to
the hydroxymethyl substituent. Thus, for R3 ) Ph, the
R:â selectivity goes from 8:92 for sulfone 29e to 76:24,
estimated as discussed above. It should be pointed out
that since these isomers are obtained in small amounts
the accuracy of this estimation is lower than that for the
2,5-cis isomers.
The nucleophilic epoxidation of phenyl-substituted
sulfonyl diene 6e with KOO-t-Bu affords a 79:21 mixture
of 22e and 23e, along with some 2,5-trans products
(Table 2, entry 16). In contrast, the treatment of sulfonyl
dihydrofuran 28e, a proposed intermediate for the above
epoxidation, with KOO-t-Bu gives a 59:41 mixture of 22e
and 23e (Table 5, entry 3). This discrepancy suggests that
at least to some extent a different reaction pathway
related to B (Scheme 5), involving sulfonyl bisoxiranes,
is operative for these aryl-substituted cases.
Con clu sion s
A novel and expedient route to tetrahydrofurans has
been developed and studied in detail. This route is based
on the serendipitous finding that the nucleophilic epoxi-
dation of hydroxy dienyl sulfoxides 4 with KOO-t-Bu
(21) A similar stereochemical outcome has been reported recently
for additions of 1,2,4-triazole to diastereomeric related sulfonyl dihy-
drofurans, see: Sanki, A. K.; Pathak, T. Synlett 2002, 1241-1244.
(22) Evans, D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G. J . Am. Chem.
Soc. 1996, 118, 4322-4343.
J . Org. Chem, Vol. 68, No. 20, 2003 7763

Ferna´ndez de la Pradilla et al.
SCHEME 10
the ubiquity of tetrahydrofurans in bioactive molecules
and the rich chemistry of these sulfur-substituted
oxiranes.2
Exp er im en ta l Section
Gen er a l P r oced u r e for Syn th esis of Hyd r oxy Dien yl
Su lfoxid es. A round-bottomed flask was charged with THF
(3.5 mL/mmol) and 2.6 equiv of freshly distilled i-Pr2NH, and
cooled to -78 °C. To the above solution was added 2.5 equiv
of n-BuLi and the resulting LDA solution (ca. 0.3 M) was
stirred at this temperature. After 10 min a solution of 1 equiv
of a mixture of dienyl sulfoxides in THF (2 mL/mmol),
previously dried over 4 Å sieves, was added dropwise slowly
(ca. 8 min/mmol of sulfoxide) to produce a pale yellow solution.
After the solution was stirred for an additional 10 min at -78
°C, 5 equiv of freshly distilled aldehyde was added dropwise
and the resulting colorless solution was stirred at this tem-
perature for 10 min. The reaction mixture was quenched with
a saturated solution of NH4Cl (2 mL/mmol) and H2O (2 mL/
mmol), then diluted with EtOAc (3 mL/mmol), and the layers
were separated. The aqueous layer was extracted with EtOAc
(3 times, 4 mL/mmol). The combined organic extracts were
washed with a saturated solution of NaCl (4 mL/mmol), dried
over MgSO4, and concentrated under reduced pressure to give
a crude product that was purified by column chromatography
with the appropriate mixture of eluents.
Syn th esis of (+)-(2E)-(1R,SS)-1-P h en yl-2-(p-tolylsu lfi-
n yl)p en ta -2,4-d ien -1-ol, 3e, a n d (-)-(2E)-(1S,SS)-1-P h en yl-
2-(p-tolylsu lfin yl)p en ta -2,4-d ien -1-ol, 4e. From i-Pr2NH
(1.7 mL, 1315 mg, 13.0 mmol) in 45 mL of anhydrous THF,
with n-BuLi (1.1 M, 11.4 mL, 12.5 mmol), a solution of dienyl
sulfoxides 1a ,2a (961 mg, 5.0 mmol) in 30 mL of THF, and
benzaldehyde (1.52 mL, 1587 mg, 15.0 mmol) according to the
general procedure, a 48:52 mixture of hydroxy dienyl sulfoxides
3e and 4e was obtained, along with ca. 15% benzyl alcohol.
Chromatographic purification (5-100% EtOAc-hexane and
CH2Cl2-40% EtOAc-CH2Cl2) gave 3e (547 mg, 37%) and 4e
(573 mg, 38%) as a white solids recrystallized from EtOAc-
hexane and 106 mg (7%) of a mixture of hydroxy dienes.
Racemic material was obtained similarly on a 30 mmol scale
(85%). Data for 3e: mp 103-104 °C; mp (racemic) 157-158
°C. Rf 0.31 (50% EtOAc-hexane), 0.42 (15% EtOAc-CH2Cl2).
[R]20D +139.5 (c 1.25). 1H NMR (200 MHz) δ 2.31 (s, 3 H), 3.39
(br, 1 H), 5.38 (dd, 1 H, J ) 10.0, 1.7 Hz), 5.53 (dd, 1 H, J )
16.7, 1.7 Hz), 5.62 (s, 1 H), 6.54 (ddd, 1 H, J ) 16.7, 11.3, 10.0
Hz), 6.95 (d, 1 H, J ) 11.3 Hz), 7.14 (d, 2 H, J ) 8.4 Hz), 7.15-
7.32 (m, 5 H), 7.41 (d, 2 H, J ) 8.2 Hz). 13C NMR (50 MHz) δ
21.3, 69.5, 125.4 (2 C), 125.9 (2 C), 126.8, 127.3, 128.2 (2 C),
128.4, 129.7 (2 C), 130.4, 133.7, 140.1, 141.1, 141.4, 146.5. IR
(film) 3360, 3080, 3060, 2920, 1630, 1595, 1490, 1450, 1300,
1180, 1080, 1030, 1010, 930, 810, 740, 700 cm-1. MS (EI) 298
[M]+, 280, 159, 141, 129, 115, 92, 91, 77 (100%), 65, 53. Anal.
Calcd for C18H18O2S: C, 72.45; H, 6.08; S, 10.75. Found: C,
72.06; H, 6.00; S, 10.43. Data for 4e: mp 134-137 °C; mp
SCHEME 11
(racemic) 148-149 °C. Rf 0.22 (50% EtOAc-hexane); 0.17 (15%
1
EtOAc-CH2Cl2). [R]20 -99.4 (c 0.80). H NMR (300 MHz) δ
D
2.29 (s, 3 H), 4.20 (br, 1 H), 5.36 (dd, 1 H, J ) 9.8, 1.8 Hz),
5.51 (dd, 1 H, J ) 16.7, 1.7 Hz), 5.64 (s, 1 H), 6.57 (ddd, 1 H,
J ) 16.7, 11.3, 9.8 Hz), 6.91 (d, 1 H, J ) 11.3 Hz), 6.90-7.15
(m, 7 H), 7.36 (d, 2 H, J ) 8.2 Hz). 13C NMR (50 MHz) δ 21.3,
69.0, 125.2, 125.5 (2 C), 126.0 (2 C), 127.1, 128.0 (2 C), 129.7
(2 C), 130.9, 133.9, 139.7, 140.7, 141.6, 147.0. IR (KBr) 3340,
3060, 1580, 1490, 1450, 1250, 1080, 1040, 1020, 935, 800, 750,
700 cm-1. MS (EI) 298 [M]+, 280, 250, 159, 141, 115, 92, 91,
produces fair yields of densely functionalized 2,5-cis-
tetrahydrofurans 18 in a single synthetic operation.
Evidence that supports the key step of this novel entry
to the tetrahydrofuran core being an unprecedented
highly stereoselective remote nucleophilic epoxidation of
the hydroxy sulfinyl diene moiety and also of simpler
sulfinyl dienes has been presented. An alternative route
to related sulfonyl dihydrofurans has been outlined and
their nucleophilic epoxidations have been studied.23 We
are currently pursuing the application of these method-
ologies to the synthesis of natural products by exploiting
(23) Further studies to improve the diastereoselectivity of the distal
electrophilic epoxidation of these hydroxy sulfonyl dienes by using
chiral dioxiranes or hydroxyl protected substrates will be carried out
for specific synthetic targets. See: (a) Frohn, M.; Shi, Y. Synthesis 2000,
1979-2000. (b) Marayama, K.; Ueda, M.; Sasaki, S.; Iwata, Y.;
Miyazawa, M.; Miyashita, M. Tetrahedron Lett. 1989, 39, 4517-4520.
7764 J . Org. Chem., Vol. 68, No. 20, 2003

Epoxidation of R′-Hydroxy Dienyl Sulfoxides
77 (100%), 65, 53. Anal. Calcd for C18H18O2S: C, 72.45; H, 6.08;
S, 10.75. Found: C, 72.64; H, 6.37; S, 10.99.
4.01 (d, 1 H, J ) 4.0 Hz), 7.36 (d, 2 H, J ) 8.4 Hz), 7.60 (d, 2
H, J ) 8.5 Hz). 13C NMR (50 MHz) δ 21.5, 44.3, 48.1, 58.3,
74.7, 124.6 (2 C), 130.4 (2 C), 137.4, 142.8. IR (film) 3000, 2920,
1600, 1490, 1450, 1290, 1250, 1090, 1050, 1020, 930, 840, 810,
720, 620 cm-1. MS (APCI) 225 [M + 1]+(100%), 139, 123. Data
Gen er a l P r oced u r e for Nu cleop h ilic Ep oxid a tion of
Vin yl a n d Dien yl Su lfoxid es a n d Su lfon es. (a ) Wit h
LiOO-t-Bu . A two-necked round-bottomed flask fitted with a
tube in T for entrance and exit of argon and a polyethylene
stopper was charged with anhydrous THF (5 mL/mmol) and
4 equiv of t-BuOOH (80% in t-BuOO-t-Bu); the resulting
mixture was cooled to 0 °C and then 5 equiv of n-BuLi was
added. The mixture was stirred at 0 °C for 10 min and a
solution of 1 equiv of the corresponding vinyl sulfoxide in THF
(5 mL/mmol), previously dried over 4 Å sieves, was added
dropwise. The reaction mixture was stirred at constant tem-
perature until starting material disappeared, monitored by
TLC. The reaction was then quenched with a 1 M solution of
Na2S2O4 (4 mL/mmol), then diluted with EtOAc (10 mL/mmol),
and the layers were separated. The aqueous layer was
extracted with EtOAc (3 times, 10 mL/mmol) and the combined
organic extracts 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,
which was purified by column chromatography on silica gel,
using a gradient of mixtures of EtOAc-hexane or EtOAc-CH2-
Cl2. Product ratios were determined by integration of well-
resolved signals in the 1H NMR of the crude reaction mixtures.
(b) With Na OO-t-Bu or KOO-t-Bu . A two-necked round-
bottomed flask fitted with a tube in T for entrance and exit of
argon and a polyethylene stopper was charged with anhydrous
THF (3-5 mL/mmol of KH) and 0.8-4 equiv of oil free NaH
or KH (washed with hexane and dried); the resulting mixture
was then cooled to 0 °C and 0.8-4 equiv of t-BuOOH (80% in
t-BuOO-t-Bu) was added. After being stirred at room temper-
ature for 20-30 min, the resulting solution (ca. 0.20 M) was
cooled to the appropriate temperature and a solution of 1 equiv
of the corresponding vinyl sulfoxide in THF (7 mL/mmol),
previously dried over 4 Å sieves, was added dropwise. The
reaction mixture was stirred at the appropriate temperature
until starting material disappeared, monitored by TLC. Isola-
tion and purification were performed as described above.
for 10a (minor isomer): Rf 0.21 (2 × 30% EtOAc-hexane).
1
[R]20 +18.3 (c 0.18). H NMR (300 MHz) δ 2.43 (s, 3 H), 2.84
D
(dd, 1 H, J ) 4.9, 2.4 Hz), 2.99 (dd, 1 H, J ) 3.8, 2.3 Hz), 3.01
(t, 1 H, J ) 3.7 Hz), 3.33 (ddd, 1 H, J ) 6.7, 3.9, 2.5 Hz), 4.00
(d, 1 H, J ) 3.7 Hz), 7.38 (d, 2 H, J ) 7.9 Hz), 7.66 (d, 2 H, J
) 8.3 Hz). 13C NMR (50 MHz) δ 21.5, 46.9, 48.5, 56.8, 74.3,
124.5 (2 C), 130.4 (2 C), 137.4, 142.7. In some experiments
from 2a with 2 equiv of KOO-t-Bu small amounts of bisepoxy
sulfone (2R,3S)-3-[(2′R)-Ep oxy]-2-(p-tolylsu lfon yl)oxir a n e,
11a (stereochemical assignment is tentative), were obtained.
Partial data for 11a : Rf 0.35 (2 × 30% EtOAc-hexane). 1H
NMR (300 MHz) δ 2.46 (s, 3 H), 2.78 (dd, 1 H, J ) 4.5, 2.7
Hz), 2.95 (dd, 1 H, J ) 7.3, 4.5 Hz), 3.01 (t, 1 H, J ) 4.5 Hz),
3.78 (m, 1 H), 4.04 (d, 1 H, J ) 4.0 Hz), 7.40 (d, 2 H, J ) 8.0
Hz), 7.84 (d, 2 H, J ) 8.3 Hz).
Syn th esis of (+)-(2R,3R,4R,5S,SS)-3,4-Ep oxy-5-p h en yl-
4-(p-tolylsu lfin yl)tetr a h yd r ofu r a n -2-m eth a n ol, 18e, (+)-
(2R,3R,4R,5S)-3,4-Ep oxy-5-p h en yl-4-(p-tolylsu lfon yl)tet-
r a h yd r ofu r a n -2-m eth a n ol, 22e, a n d (+)-(2R,5S,SS)-4-(p-
Tolylsu lfin yl)-5-ph en yl-2,5-dih ydr ofu r an -2-m eth an ol, 16e.
(a ) With 1.8 equ iv of KOO-t-Bu fr om -20 to 0 °C. From a
solution of hydroxy sulfinyl diene 4e (135 mg, 0.452 mmol),
in THF (2.5 mL), and a cold (-20 to 0 °C) 0.2 M THF solution
of KOO-t-Bu (1.8 equiv) (50 min), according to the general
procedure, a 12:77:11 mixture of sulfinyl dihydrofurans and
sulfinyl and sulfonyl tetrahydrofurans 16e, 18e, and 22e was
obtained, along with a significant amount (ca. 25%) of bisep-
oxides 12e′,12e′′ (60:40 sulfoxide:sulfone, respectively). Puri-
fication by chromatography (30-50% EtOAc-hexane) gave
16e-17e (6 mg, 4%, 80:20 mixture of diastereomers), 18e-
20e (38 mg, 25%, 77:18:5 mixture of diastereomers), and 22e
(6 mg, 4%, 65:35 mixture of diastereomers), all obtained as
colorless oils. In addition bisepoxides 12e′,12e′′ (S ) sulfoxide
and sulfone) were also isolated and they are assigned tenta-
tively. (b) With 1.8 equ iv of KOO-t-Bu a t 0 °C. From a
solution of hydroxy sulfinyl diene 4e (116 mg, 0.389 mmol),
in THF (6.0 mL), and a cold (0 °C) 0.2 M THF solution of KOO-
t-Bu (1.8 equiv) (35 min), according to the general procedure,
an 87:13 mixture of sulfinyl and sulfonyl tetrahydrofurans 18e
and 22e was obtained. Purification by chromatography (15-
100% EtOAc-hexane) gave 18e-20e (46 mg, 36%, 74:14:12
mixture of diastereomers) and 22e (8 mg, 6%, 68:32 mixture
of diastereomers), all obtained as colorless oils. A second
careful chromatography afforded diastereomerically enriched
18e (81:14:5). (c) With 3.0 equ iv of KOO-t-Bu a t 0 °C. From
a solution of hydroxy sulfinyl diene 4e (60 mg, 0.20 mmol), in
THF (4.0 mL), and a cold (0 °C) 0.2 M THF solution of KOO-
t-Bu (3.0 equiv) (30 min), according to the general procedure,
an 79:21 mixture of sulfinyl and sulfonyl tetrahydrofurans 18e
and 22e was obtained in a complex crude mixture. Purification
by chromatography (0-40% EtOAc-CH2Cl2) gave 18e (8 mg,
12%, mixture of diastereomers). (d ) With 2.0 equ iv of KOO-
t-Bu a t 0 °C, 4 m m ol Sca le. From a solution of hydroxy
sulfinyl diene 4e (1194 mg, 4 mmol), in THF (46.0 mL), and a
cold (0 °C) 0.2 M THF solution of KOO-t-Bu (2.0 equiv) (25
min), according to the general procedure, an 85:15 mixture of
sulfinyl and sulfonyl tetrahydrofurans 18e and 22e was
obtained. Purification by chromatography (3-100% EtOAc-
CH2Cl2) gave 18e (318 mg, 24%, recrystallized from 30%
EtOAc-hexane to yield the pure major isomer) and 22e (105
mg, 8%, recrystallized from 30% EtOAc-hexane to yield the
pure major isomer). Data for 16e (major isomer): Rf 0.14 (75%
Syn th esis of (+)-(2R,3S,SS)-2-(p-Tolylsu lfin yl)-3-vin yl-
oxir a n e, 8a , (+)-(2R,3S,SS)-3-[(2′R)-Ep oxy]-2-(p-toylsu lfi-
n yl)oxir a n e, 9a , a n d (+)-(2R,3S,SS)-3-[(2′S)-Ep oxy]-2-(p-
tolylsu lfin yl)oxir a n e, 10a . (a ) 1 equ iv of KOO-t-Bu . From
a solution of sulfinyl diene 2a (58 mg, 0.302 mmol), in THF
(2.0 mL), and a cold (-78 to 0 °C) 0.2 M THF solution of KOO-
t-Bu (1 equiv) (35 min), according to the general procedure, a
9:91 mixture of 8a and 9a ,10a was obtained at 71% conversion.
Purification by chromatography (5-40% EtOAc-hexane) gave
monoepoxide 8a (2 mg, 3%) as a colorless oil and an 84:16
mixture of bisepoxides 9a :10a (22 mg, 33%) as a colorless oil.
A second careful chromatography allowed for the separation
of the bisepoxides. Stereochemical assignments are tentative.
(b) 2 equ iv of KOO-t-Bu . From a solution of sulfinyl diene
2a (39 mg, 0.203 mmol), in THF (2.0 mL), and a cold (-20 to
0 °C) 0.2 M THF solution of KOO-t-Bu (2 equiv) (65 min),
according to the general procedure, a 60:40 mixture of 8a and
9a ,10a was obtained at 91% conversion. Purification by
chromatography (5-40% EtOAc-hexane) gave monoepoxide
8a (12 mg, 28%) as a colorless oil and a separable 82:18
mixture of bisepoxides 9a :10a (10 mg, 22%) as a colorless oil.
Data for 8a : Rf 0.35 (2 × 30% EtOAc-hexane). [R]20 +39.3
D
1
(c 0.37). H NMR (300 MHz) δ 2.40 (s, 3 H), 3.66 (ddt, 1 H, J
) 8.4, 3.9, 0.7 Hz), 4.05 (d, 1 H, J ) 3.9 Hz), 5.55 (dt, 1 H, J
) 3.9, 0.8 Hz), 5.64 (dt, 1 H, J ) 17.1, 0.8 Hz), 5.99 (ddd, 1 H,
J ) 17.2, 10.4, 8.4 Hz), 7.33 (d, 2 H, J ) 8.5 Hz), 7.52 (d, 2 H,
J ) 8.2 Hz). 13C NMR (75 MHz) δ 21.4, 58.4, 76.6, 123.5, 124.3
(2 C), 128.5, 130.2 (2 C), 131.1, 142.2. IR (film) 3060, 2920,
1
1600, 1490, 1440, 1320, 1160, 1090, 1055, 950, 815, 670 cm-1
.
EtOAc-hexane). H NMR (300 MHz) δ 1.87 (m, 1 H), 2.39 (s,
Data for 9a (major isomer): Rf 0.16 (2 × 30% EtOAc-hexane).
3 H), 3.77-3.84 (m, 2 H), 5.04 (dddd, 1 H, J ) 8.3, 4.6, 3.8, 1.6
Hz), 5.19 (dd, 1 H, J ) 4.5, 2.1 Hz), 6.75 (dd, 1 H, J ) 2.1, 1.6
Hz), 7.10-7.44 (m, 9 H). 13C NMR (50 MHz) δ 21.4, 64.5, 86.2,
87.0, 125.5 (2 C), 128.1 (2 C), 128.7 (2 C), 129.1, 130.1 (2 C),
1
[R]20 +86.7 (c 0.38). H NMR (300 MHz) δ 2.42 (s, 3 H), 2.74
D
(dd, 1 H, J ) 4.9, 2.6 Hz), 2.96 (dd, 1 H, J ) 4.9, 4.3 Hz), 3.02
(dd, 1 H, J ) 6.1, 3.9 Hz), 3.37 (ddd, 1 H, J ) 6.2, 4.1, 2.6 Hz),
J . Org. Chem, Vol. 68, No. 20, 2003 7765

Ferna´ndez de la Pradilla et al.
131.0, 137.9, 137.9, 142.7, 149.4. IR (CCl4) 3440, 3040, 3020,
2900, 2860, 1590, 1490, 1450, 1390, 1270, 1110, 1070, 1050,
1000, 800, 750, 725, 690 cm-1. MS (ES) 337 [M + Na]+ (100%),
315 [M + 1]+. Partial data for 17e (minor isomer): 1H NMR
(300 MHz) δ 3.68 (dd, 2 H, J ) 11.7, 4.5 Hz), 5.28 (s, 1 H),
6.72 (t, 1 H, J ) 1.8 Hz). Data for 18e (major isomer): mp
7.18 (d, 2 H, J ) 8.6 Hz), 7.53 (d, 2 H, J ) 8.3 Hz). 13C NMR
(50 MHz) δ 21.6, 47.5, 48.3, 69.1, 125.5 (2 C), 127.6, 128.1 (2
C), 128.3 (2 C), 129.8 (2 C), 136.0, 139.9, 141.8, 144.6, 148.1.
IR (KBr) 3480, 1630, 1600, 1490, 1445, 1315, 1300, 1145, 1070,
1055, 930, 840, 805, 755, 715, 700, 690 cm-1. MS (ES) 353 [M
+ Na]+. Anal. Calcd for C18H18O4S: C, 65.43; H, 5.49; S, 9.71.
Found: C, 65.12; H, 5.70; S, 9.55. Data for 27e: mp 93-94
(racemic) 139-140 °C. Rf 0.20 (40% EtOAc-CH2Cl2), 0.12 (50%
1
1
EtOAc-hexane). [R]20 +36.0 (c 1.00). H NMR (300 MHz) δ
°C. Rf 0.14 (30% EtOAc-hexane). H NMR (300 MHz) δ 2.39
D
(s, 3 H), 2.73 (dd, 1 H, J ) 5.5, 2.4 Hz), 2.98 (dd, 1 H, J ) 5.4,
4.3 Hz), 3.09 (d, 1 H, J ) 5.7 Hz), 3.54 (ddd, 1 H, J ) 8.4, 4.3,
2.4 Hz), 5.81 (d, 1 H, J ) 5.7 Hz), 6.59 (d, 1 H, J ) 8.3 Hz),
7.18-7.24 (m, 7 H), 7.62 (d, 2 H, J ) 8.3 Hz). 13C NMR (50
MHz) δ 21.5, 47.3, 48.6, 69.4, 125.9 (2 C), 127.8, 128.2 (2 C),
128.4 (2 C), 129.8 (2 C), 135.8, 139.5, 141.9, 144.7, 148.2. IR
(KBr) 3380, 1570, 1470, 1435, 1300, 1280, 1270, 1160, 1130,
1120, 1065, 1025, 950, 850, 810, 790, 745, 680, 650 cm-1. MS
(ES) 353 [M + Na]+. Anal. Calcd for C18H18O4S: C, 65.43; H;
5.49, S, 9.71. Found: C, 65.38; H, 5.54; S, 9.62.
Gen er a l P r oced u r e for Cycliza tion of Mon oep oxid es
w ith CSA. To a solution of the monoepoxide in CH2Cl2 (5 mL/
mmol) at room temperature under an atmosphere of Argon
was added camphorsulfonic acid (CSA, 0.2 equiv). The mixture
was stirred at room temperature and monitored by TLC until
completion and then quenched with a saturated solution of
NaHCO3 (5 mL/mmol). The layers were separated, the aqueous
layer was extracted with CH2Cl2 (3 times, 5 mL/mmol), and
the combined organic extracts were washed with saturated
NaCl (2 times, 5 mL/mmol), dried over anhydrous MgSO4, and
concentrated to give a crude product that was purified by
column chromatography on silica gel or recrystallization.
Syn th esis of (()-(2R,5S)-5-P h en yl-4-(p-tolylsu lfon yl)-
2,5-d ih yd r ofu r a n -2-m eth a n ol, 28e. From monoepoxide 26e
(297 mg, 0.9 mmol), with CSA (42 mg, 0.18 mmol, 0.2 equiv),
according to the general procedure (2 h), sulfonyl dihydrofuran
28e (295 mg, 99%) was obtained after purification by chro-
matography (10-60% EtOAc-hexane) as a white solid that
was recrystallized from EtOAc-hexane. Data for 28e: mp
112-113 °C. Rf 0.30 (75% EtOAc-hexane). 1H NMR (300 MHz)
δ 1.82 (dd, 1 H, J ) 6.6, 6.3 Hz), 2.32 (s, 3 H), 3.86 (m, 2 H),
5.05 (m, 1 H), 5.87 (dd, 1 H, J ) 5.0, 2.2 Hz), 6.97-7.26 (m, 10
H). DNOE between H-2/H-5 1.5%, between H-2/H-3 5.0%,
between H-5/H-2 1.0%. 13C NMR (50 MHz) δ 21.4, 63.7, 85.7,
86.4, 127.8 (2 C), 128.2 (4 C), 128.7, 129.3 (2 C), 135.7, 137.1,
139.9, 144.3, 145.5. IR (film) 3501, 2925, 1596, 1457, 1319,
1154, 1122, 1084, 813, 761, 701, 678 cm-1. MS (ES) 353 [M +
Na]+. Anal. Calcd for C18H18O4S: C, 65.43; H; 5.49, S, 9.71.
Found: C, 65.72; H, 5.71; S, 9.95.
2.20 (br s, 1 H), 2.39 (s, 3 H), 3.87 (t, 2 H, J ) 5.0 Hz), 4.29 (t,
1 H, J ) 5.2 Hz), 4.48 (s, 1 H), 4.60 (s, 1 H), 7.25-7.45 (m, 9
H). 13C NMR (50 MHz) δ 21.6, 62.5, 67.2, 80.0, 81.7, 83.2, 126.6,
128.8 (2 C), 129.3, 129.7 (2 C), 129.9, 135.4, 135.6, 143.4. IR
(CHCl3) 3400, 3010, 2920, 2890, 1595, 1490, 1450, 1215, 1080,
1050, 1010, 920, 805, 750, 700, 660, 620 cm-1. MS (EI) 330,
282, 191, 161, 139 (100%), 107, 105, 91, 77, 65, 51. Anal. Calcd
for C18H18O4S: C, 65.44; H, 5.49; S, 9.70. Found: C, 65.26; H,
5.52; S, 9.60. Partial data for 19e (first minor isomer): 1H
NMR (300 MHz) δ 2.29 (s, 3 H), 3.80-3.90 (m, 2 H), 4.11 (td,
1 H, J ) 5.5, 0.8 Hz), 4.34 (d, 1 H, J ) 0.7 Hz), 4.99 (s, 1 H).
Partial data for 20e (second minor isomer): 1H NMR (300
MHz) δ 2.40 (s, 3 H), 3.80-3.90 (m, 2 H), 4.50 (d, 1 H, J ) 0.7
Hz), 4.53 (t, 1 H, J ) 5.6 Hz), 4.55 (s, 1 H). The data for sulfonyl
tetrahydrofurans 22e-24e are described below. Data for
(1S ,2R ,3S ,S S )-2,3,4,5,-d ie p oxy-1-p h e n yl-2-(p -t olylsu l-
fin yl)p en ta n -1-ol, 12e′ (major): Rf 0.20 (2 × 50% EtOAc-
1
hexane). H NMR (300 MHz) δ 2.39 (s, 3 H), 2.72 (dd, 1 H, J
) 5.0, 2.7 Hz), 2.84 (dd, 1 H, J ) 4.9, 4.2 Hz), 3.17 (ddd, 1 H,
J ) 5.0, 4.2, 2.6 Hz), 3.30 (d, 1 H, J ) 5.1 Hz), 5.09 (s, 1 H),
7.25-7.50 (m, 8 H), 8.08 (d, 1 H, J ) 8.4 Hz). 13C NMR (75
MHz) δ 21.6, 44.8, 48.1, 59.8, 70.4, 80.5, 126.2 (2 C), 126.5 (2
C), 128.5, 128.7 (2 C), 129.9 (2 C), 130.1, 133.6, 34.5, 138.1,
143.1. Partial data for (1S,2R,3S)-2,3,4,5,-d iep oxy-1-p h en yl-
2-(p-tolylsu lfon yl)p en ta n -1-ol, 12e′′ (minor): Rf 0.48 (2 ×
50% EtOAc-hexane). 1H NMR (300 MHz) δ 2.36 (s, 3 H), 2.88
(m, 2 H), 3.30 (m, 1 H), 3.40 (d, 1 H, J ) 4.8 Hz), 5.06 (s, 1 H),
7.20-7.50 (m, 7 H), 8.10 (d, 1 H, J ) 8.4 Hz).
Gen er a l P r oced u r e for Oxid a tion /Ep oxid a tion of Hy-
d r oxy Dien yl Su lfoxid es w ith m -CP BA. To a solution of
the sulfoxide in toluene (10 mL/mmol) was added 4.0 equiv of
70% m-CPBA, and the reaction mixture was stirred at room
temperature and monitored by TLC until disappearance of the
sulfonyl diene. The reaction was quenched with 1 M aqueous
Na2S2O4 (5 mL/mmol) and a saturated solution of NaHCO3 (5
mL/mmol) and water (5 mL/mmol). The layers were separated
and the aqueous phase was extracted with EtOAc (2 times, 5
mL/mmol). The combined organic layers were washed with
saturated NaHCO3 mixed with water (50:50, 5 times, 5 mL/
mmol) and a saturated solution of NaCl (4 mL/mmol), dried
over MgSO4, filtered, and concentrated under reduced pressure
to give a crude product that was purified by column chroma-
tography. When the reaction was carried out on a larger scale
(>10 mmol), the reaction was quenched with 1 M Na2S2O4 (5
mL/mmol), stirred for 20 min, and filtered to remove m-
chlorobenzoic acid. The solid was washed thoroughly with
toluene and the crude product was then isolated as described
above.
Syn th esis of (()-(2S,5S)-5-P h en yl-4-(p-tolylsu lfon yl)-
2,5-d ih yd r ofu r a n -2-m eth a n ol, 29e. From monoepoxide 27e
(76 mg, 0.23 mmol), with CSA (11 mg, 0.05 mmol, 0.2 equiv),
according to the general procedure (1.5 h), sulfonyl dihydro-
furan 29e (73 mg, 96%) was obtained after recrystallization
of the crude with 80% Et2O-hexane. Data for 29e: mp 103-
1
104 °C. Rf 0.30 (75% EtOAc-hexane). H NMR (300 MHz) δ
1.89 (dd, 1 H, J ) 6.6, 6.3 Hz), 2.32 (s, 3 H), 3.71-3.86 (m, 2
H), 5.20-5.25 (m, 1 H), 5.92 (dd, 1 H, J ) 6.0, 2.0 Hz), 6.95-
7.31 (m, 10 H). DNOE between H-5/CH2-OH 0.4%, between
H-2/CH2-OH 3.1%, between H-2/H-3 4.2%. 13C NMR (50 MHz)
δ 21.4, 64.0, 86.5, 86.7, 127.5 (2 C), 127.8 (2 C), 128.2 (2 C),
128.5, 129.3 (2 C), 135.8, 137.6, 139.2, 144.3, 146.0. IR (KBr)
3524, 2876, 1628, 1594, 1458, 1379, 1290, 1150, 1055, 764, 703,
684, 592, 569, 527 cm-1. MS (ES) 353 [M + Na]+. Anal. Calcd
for C18H18O4S: C, 65.43; H, 5.49, S, 9.71. Found: C, 65.27; H,
5.44; S, 9.58.
Syn th esis of (()-(1S,4S)-(2E)-4,5-Ep oxy-1-p h en yl-2-(p-
tolylsu lfon yl)p en t-2-en -1-ol, 26e, a n d (()-(1S,4R)-(2E)-4,5-
Epoxy-1-ph en yl-2-(p-tolylsu lfon yl)pen t-2-en -1-ol, 27e. From
a mixture of sulfinyl dienes 3e and 4e (298 mg, 1 mmol), with
m-CPBA (986 mg, 4 mmol, 4 equiv), according to the general
procedure, an 80:20 mixture of monoepoxides (26e and 27e)
and dihydrofurans (28e and 29e) was obtained. Purification
by chromatography (10-50% EtOAc-hexane) gave 26e (116
mg, 37%) as a white solid that was recrystallized from EtOAc-
hexane, 27e (75 mg, 24%) as a white solid that was recrystal-
lized from EtOAc-hexane, and a mixture of dihydrofurans 28e
and 29e (48 mg, 15%). Data for 26e: mp 104-105 °C. Rf 0.17
(30% EtOAc-hexane). 1H NMR (200 MHz) δ 2.37 (s, 3 H), 2.68
(dd, 1 H, J ) 5.3, 2.5 Hz), 2.85 (dd, 1 H, J ) 5.4, 4.3 Hz), 3.41
(d, 1 H, J ) 6.7 Hz), 3.70 (ddd, 1 H, J ) 8.0, 4.3, 2.5 Hz), 5.80
(d, 1 H, J ) 6.7 Hz), 6.61 (d, 1 H, J ) 7.9 Hz), 7.18 (s, 5 H),
Syn th esis of (()-(2R,3R,4R,5S)-3,4-Ep oxy-5-p h en yl-4-
(p-tolylsu lfon yl)tetr a h yd r ofu r a n -2-m eth a n ol, 22e, a n d
(()-(2R,3S,4S,5S)-3,4-Ep oxy-5-p h en yl-4-(p-tolylsu lfon yl)-
tetr a h yd r ofu r a n -2-m eth a n ol, 23e. From a solution of sul-
fonyl dihydrofuran 28e (66 mg, 0.2 mmol) in THF (1.4 mL)
and a cold (-65 °C) 0.2 M THF solution of LiOO-t-Bu (4 equiv),
after warming up to 0 °C (6 h), according to the general
procedure, a 91:9 mixture of sulfonyl tetrahydrofurans 22e and
7766 J . Org. Chem., Vol. 68, No. 20, 2003

Epoxidation of R′-Hydroxy Dienyl Sulfoxides
23e and traces of furan 31e were obtained. Purification by
chromatography (15-40% EtOAc-hexane) gave impure 31e
(3 mg, 5%) as a colorless oil, a mixture of 22e and 23e (20 mg,
29%), and pure 22e (24 mg, 35%) as a white solid that was
recrystallized from EtOAc-hexane. From a solution of sulfonyl
dihydrofuran 28e (66 mg, 0.2 mmol) in THF (1.4 mL) and a
cold (0 °C) 0.2 M THF solution of NaOO-t-Bu (3 equiv) (25
min), according to the general procedure, a 59:41 mixture of
sulfonyl tetrahydrofurans 22e and 23e was obtained. Purifica-
tion by chromatography (20-30% EtOAc-hexane) gave 23e
(4 mg, 6%) as a colorless oil, a mixture of 22e and 23e (23 mg,
33%), and pure 22e (14 mg, 20%) as a white solid that was
recrystallized from EtOAc-hexane. From a solution of sulfonyl
dihydrofuran 28e (66 mg, 0.2 mmol) in THF (1.4 mL) and a
cold (-40 to -15 °C) 0.2 M THF solution of KOO-t-Bu (2 equiv)
(50 min), according to the general procedure, a 59:41 mixture
of sulfonyl tetrahydrofurans 22e and 23e was obtained.
Purification by chromatography (15-30% EtOAc-hexane)
gave 23e (14 mg, 20%) as a colorless oil, a mixture of 22e and
23e (28 mg, 40%), and pure 22e (13 mg, 18%) as a white solid
that was recrystallized from EtOAc-hexane. Data for 22e: mp
133-134 °C. Rf 0.26 (50% EtOAc-hexane). 1H NMR (300 MHz)
δ 1.85 (br s, 1 H), 2.41 (s, 3 H), 3.93 (d, 2 H, J ) 5.5 Hz), 4.26
(t, 1 H, J ) 5.5 Hz), 4.41 (s, 1 H), 5.06 (s, 1 H), 7.20-7.37 (m,
9 H). 13C NMR (50 MHz) δ 21.7, 62.5, 67.4, 78.6, 80.6, 82.5,
128.1 (2 C), 128.9 (2 C), 129.0 (2 C), 129.3, 129.6 (2 C), 133.8,
135.1, 145.5. IR (CHCl3) 3530, 3030, 2930, 1600, 1500, 1460,
1330, 1310, 1220, 1160, 1090, 1050, 990, 940, 820, 760, 700,
670, 640 cm-1. MS (EI) 346 [M]+, 315, 299, 263, 191, 161, 139,
131, 105, 91 (100%), 85, 77, 65, 57. Data for 23e: Rf 0.27 (50%
hexane) gave 25e (38 mg, 73%) as a white solid that was
recrystallized from EtOAc-hexane and 24e (7 mg, 14%) as a
colorless oil. From a solution of sulfonyl dihydrofuran 29e (50
mg, 0.15 mmol) in THF (1.0 mL) and a cold (0 °C) 0.2 M THF
solution of NaOO-t-Bu (3 equiv) (20 min), according to the
general procedure, a 77:23 mixture of sulfonyl tetrahydro-
furans 25e and 24e was obtained. Purification by chromatog-
raphy (20-30% EtOAc-hexane) gave 25e (31 mg, 59%) as a
white solid that was recrystallized from EtOAc-hexane and
24e (5 mg, 10%) as a colorless oil. From a solution of sulfonyl
dihydrofuran 29e (40 mg, 0.12 mmol) in THF (1.0 mL) and a
cold (-40 to -30 °C) 0.2 M THF solution of KOO-t-Bu (2 equiv)
(20 min), according to the general procedure, a 92:8 mixture
of sulfonyl tetrahydrofurans 25e and 24e was obtained.
Purification by chromatography (15-30% EtOAc-hexane)
gave 25e (32 mg, 77%) as a white solid that was recrystallized
from EtOAc-hexane and 24e (3 mg, 7%) as a colorless oil. Data
1
for 24e: Rf 0.20 (50% EtOAc-hexane). H NMR (200 MHz) δ
1.86 (br s, 1 H), 2.42 (s, 3 H), 3.81 (d, 2 H, J ) 5.5 Hz), 4.45 (s,
1 H), 4.54 (t, 1 H, J ) 5.6 Hz), 4.98 (s, 1 H), 7.19-7.40 (m, 7
H), 7.50 (d, 2 H, J ) 8.3 Hz). 13C NMR (50 MHz) δ 21.7, 61.4,
63.7, 77.2, 77.7, 80.6, 128.1 (2 C), 128.5 (2 C), 129.0 (2 C), 129.4,
129.8 (2 C), 133.7, 136.1, 145.8. IR (film) 3526, 3065, 2925,
1595, 1456, 1331, 1160, 1087, 1052, 814, 764, 700, 667, 588
cm-1. MS (ES) 369 [M + Na]+. Anal. Calcd for C18H18O5S: C,
62.41; H, 5.24, S, 9.26. Found: C, 62.32; H, 5.29; S, 9.42. Data
for 25e: mp 120-121 °C. Rf 0.25 (50% EtOAc-hexane). 1H
NMR (300 MHz) δ 1.85 (dd, 1 H, J ) 6.1, 5.1 Hz), 2.29 (s, 3
H), 3.85-3.89 (m, 2 H), 4.34 (dd, 1 H, J ) 4.8, 4.6 Hz), 4.35 (s,
1 H), 5.51 (s, 1 H), 6.98 (d, 2 H, J ) 8.4 Hz), 7.07-7.24 (m, 5
H), 7.34 (d, 2 H, J ) 8.3 Hz). DNOE between CH2-OH/H-5
3.7% and between CH2-OH/H-3 3.7%. 13C NMR (50 MHz) δ
21.5, 62.2, 64.6, 76.8, 77.4, 78.3, 128.0 (2 C), 128.5 (2 C), 128.6
(2 C), 128.8, 129.2 (2 C), 132.9, 133.9, 145.2. IR (KBr) 3526,
2925, 1596, 1456, 1319, 1157, 1099, 1048, 968, 743, 671, 607,
582 cm-1. MS (ES) 369 [M + Na]+ (100%), 347 [M + 1]+. Anal.
Calcd for C18H18O5S: C, 62.41; H, 5.24, S, 9.26. Found: C,
62.62; H, 5.45; S, 9.12.
1
EtOAc-hexane). H NMR (300 MHz) δ 1.87 (ap t, 1 H, OH),
2.29 (s, 3 H), 3.89 (t, 2 H, J ) 5.4 Hz), 4.20 (t, 1 H, J ) 5.2
Hz), 4.41 (s, 1 H), 5.35 (s, 1 H), 6.96 (d, 2 H, J ) 7.9 Hz), 7.18-
7.25 (m, 5 H), 7.29 (d, 2 H, J ) 8.3 Hz). 13C NMR (50 MHz) δ
21.6, 61.5, 63.6, 76.5, 77.3, 77.6, 128.2 (2 C), 128.5 (2 C), 128.7
(2 C), 129.1, 129.2 (2 C), 132.8, 133.4, 145.2. IR (film) 3524,
3066, 2885, 1596, 1495, 1458, 1401, 1329, 1305, 1159, 1129,
1087, 1053, 813, 756, 700, 673, 594 cm-1. MS (ES) 369 [M +
Na]+. Anal. Calcd for C18H18O5S: C, 62.41; H, 5.24, S, 9.26.
Found: C, 62.21; H, 5.02; S, 9.37. Partial data for 31e (from
a 41:59 mixture of 31e and 23e): Rf 0.27 (50% EtOAc-
Ack n ow led gm en t. This research was supported by
DGICYT (PPQ2000-1330 and BQU2001-0582) and CAM
(08.5/0079.1/2000 and 08.5/0028/2003 2). We warmly
thank J ANSSEN-CILAG for generous additional sup-
port. We thank CAM for a doctoral fellowship to C. M.
We are grateful to Professor S. Valverde and Dr. J . C.
Lo´pez (IQO, CSIC) for encouragement and support.
1
hexane). H NMR (200 MHz) δ 2.34 (s, 3 H), 4.61 (d, 2 H, J )
15.6 Hz), 6.71 (s, 1 H), 7.05-7.44 (m, 7 H), 7.65 (d, 2 H, J )
8.4 Hz).
Syn t h esis of (()-(2S,3R,4R,5S)-3,4-E p oxy-5-p h en yl-4-
(p-tolylsu lfon yl)tetr a h yd r ofu r a n -2-m eth a n ol, 24e, a n d
(()-(2S,3S,4S,5S)-3,4-Ep oxy-5-p h en yl-4-(p-tolylsu lfon yl)-
tetr a h yd r ofu r a n -2-m eth a n ol, 25e. From a solution of sul-
fonyl dihydrofuran 29e (50 mg, 0.15 mmol) in THF (1.0 mL)
and a cold (-65 to 0 °C) 0.2 M THF solution of LiOO-t-Bu (4
equiv) (21 h), according to the general procedure, a 76:24
mixture of sulfonyl tetrahydrofurans 25e and 24e was ob-
tained. Purification by chromatography (15-40% EtOAc-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization for new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
J O0349173
J . Org. Chem, Vol. 68, No. 20, 2003 7767