Sulfur-directed enantioselective synthesis of functionalized dihydropyrans

Article abstract of DOI:10.1021/jo801029q

(Chemical Equation Presented) The highly selective base-promoted cyclization of enantiopure sulfinyl dienols affords allylic sulfinyl dihydropyrans. The scope of this methodology, including the preparation of seven-membered rings, has been studied in dept

Full text of DOI:10.1021/jo801029q

Sulfur-Directed Enantioselective Synthesis of Functionalized
Dihydropyrans
´
Roberto Fernández de la Pradilla,* Mariola Tortosa, Nadia Lwoff, Miguel A. del Aguila,
and Alma Viso
Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la CierVa, 3, 28006 Madrid, Spain
iqofp19@iqog.csic.es
ReceiVed May 14, 2008
The highly selective base-promoted cyclization of enantiopure sulfinyl dienols affords allylic sulfinyl
dihydropyrans. The scope of this methodology, including the preparation of seven-membered rings, has
been studied in depth. The reactivity of our sulfinyl dihydropyrans toward oxidation, imination, and
dihydroxylation has been explored, and thus several routes to densely functionalized pyran derivatives
have been outlined. The reactivity of allylic dihydropyranyl sulfones and sulfoximines in SN2′ processes
with organocuprates has been examined. The displacement products were obtained with good regio- and
stereoselectivity and fair to good yields. The reactivity of these products to dihydroxylation opens new
possibilities to access enantiopure polyhydroxylated tetrahydropyrans that could be of interest for the
synthesis of natural products.
Introduction
Several years ago, while studying the synthesis of hydroxy
sulfinyl dienes from epoxy vinyl sulfoxides, we observed that
vinyl oxiranes A (Scheme 1) displayed an undesired SN2′
reactivity with complex secondary alcohols existing in the
reaction media to produce adducts B.3 Although at that time
the stereochemical reaction pathway was not investigated, the
Dihydro- and tetrahydropyrans are key building blocks of
many natural and bioactive products that exhibit a broad variety
of biological activities and can be isolated from numerous
sources.1 These bioactive compounds often present multisub-
stituted heterocyclic rings with a defined stereochemistry, and
so the development of new methods to access enantiopure
dihydro- and tetrahydropyrans has remained a current challenge
for synthetic organic chemistry.2
(2) For recent references on the construction of dihydro- and tetrahydropyrans,
see: (a) Van Orden, L. J.; Patterson, B. D.; Rychnovsky, S. D. J. Org. Chem.
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10.1021/jo801029q CCC: $40.75 2008 American Chemical Society
Published on Web 07/29/2008

EnantioselectiVe Synthesis of Functionalized Dihydropyrans
treatment with base.7,8 Dienols E are available by Stille coupling
between vinyl stannanes and stereodefined Z- or E-iodo alkenyl
sulfoxides H, which are prepared from alkynyl sulfoxides I by
stereocontrolled hydrostannylation and tin-halogen exchange.
In this paper we describe in full our results on the efficient base-
induced cyclization of hydroxy dienyl sulfoxides E to produce
good to excellent yields of allylic sulfoxides F and G.9 In
addition, we have outlined a simple protocol for producing
enantiopure sulfones related to D from intermediates F and have
examined several potentially useful transformations of these
compounds. Finally, we have addressed the allylic displacements
of enantiopure sulfones and sulfoximines related to F with
organocuprates. Interestingly, this work brings to light that each
sulfur moiety -sulfoxide, sulfone, sulfoximine- exerts a
particular control on the stereochemical outcome of the cy-
clizations and SN2′ displacements.
SCHEME 1. Proposed Sulfinyl-Mediated Synthesis of
Dihydropyrans
Results and Discussion
Preparation of Hydroxy Dienyl Sulfoxides. The required
iodo alkenyl sulfoxides were prepared from menthyl p-toluene
sulfinate in three steps as shown in Scheme 2. From com-
mercially available alkynes 1a and 1b, alkynyl sulfoxides 2a
and 2b were prepared following the literature procedure.10
Palladium-catalyzed hydrostannylation of the alkynyl sulfoxides
led to E vinyl stannanes 3a and 3b as major products along
with small amounts of the regioisomeric products. The non-
catalyzed hydrostannylation proceeded with lower yields due
to the formation of variable mixtures of the expected Z vinyl
stannanes 4a and 4b and their E isomers, and in the case of 2a,
also a considerable amount of an unexpected regioisomeric
product (see Supporting Information). Because of the low
solubility of substrate 2a in hexane, the usual solvent for these
reactions, toluene had to be used. This change of solvent might
be the reason for the loss of regioselectivity observed in the
fact that only one isomer was formed was significant and
indicated that the process occurred with high selectivity. In
connection with our interest in the design of sulfoxide-based
synthetic procedures, especially those that allow for multiple
chirality-transfer operations,4 and with our involvement in the
synthesis of functionalized tetrahydrofurans,5 we envisioned that
an intramolecular variant of this process entailing the cyclization
of cis-hydroxy oxiranes C to hydroxy dihydropyrans D could
be a viable process. If successful, we perceived that dihydro-
pyrans D had a useful array of functionality for synthetic
purposes either at sulfoxide or sulfone oxidation states.6
(6) For recent reviews on sulfoxide chemistry, see: (a) Carren˜o, M. C. Chem.
ReV. 1995, 95, 1717–1760. (b) Garc´ıa Ruano, J. L.; Cid de la Plata, B. Top.
Curr. Chem. 1999, 204, 1–126. (c) Procter, D. J. J. Chem. Soc., Perkin Trans.
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Org. Chem. 2002, 350, 3507–3535. (g) Hanquet, G.; Colobert, F.; Lanners, S.;
Solladie´, G. ArkiVoc 2003, 328–401. (h) Fernández, I.; Khiar, N. Chem. ReV.
2003, 103, 3651–3706. (i) Forristal, I. J. Sulfur Chem. 2005, 26, 163–195. (j)
Rodr´ıguez Rivero, M.; Adrio, J.; Carretero, J. C. Synlett 2005, 2, 6–41. (k)
Pellissier, H. Tetrahedron 2006, 62, 5559–5601. (l) Feldman, K. S. Tetrahedron
2006, 62, 5003–5034. (m) Pellissier, H. Tetrahedron 2007, 63, 1297–1330. (n)
Nenajdenko, V. G.; Krasovskiy, A. L.; Balenkova, E. S. Tetrahedron 2007, 63,
12481–12539. For recent reviews on sulfones, see: (o) Back, T. G. Tetrahedron
2001, 57, 5263–5301. (p) Chemla, F. J. Chem. Soc. Perkin Trans. 1 2002, 275–
299.
Alternatively, dienyl sulfoxides E were also identified as
suitable precursors of dihydropyrans F and oxepines G with a
stereochemically labile allylic sulfoxide functionality, upon
(3) (a) Marino, J P.; Anna, L. J.; Fernández de la Pradilla, R.; Mart´ınez,
M. V.; Montero, C.; Viso, A. Tetrahedron Lett. 1996, 37, 8031–8034. (b)
Fernández de la Pradilla, R.; Mart´ınez, M. V.; Montero, C.; Viso, A. Tetrahedron
Lett. 1997, 38, 7773–7776. (c) Marino, J. P.; Anna, L. J.; Fernández de la Pradilla,
R.; Mart´ınez, M. V.; Montero, C.; Viso, A. J. Org. Chem. 2000, 65, 6462–
6473. (d) Fernández de la Pradilla, R.; Buergo; M, V.; Mart´ınez, M. V.; Montero,
C.; Tortosa, M.; Viso, A. J. Org. Chem. 2004, 69, 1978–1986.
(4) (a) Fernández de la Pradilla, R.; Baile, R.; Tortosa, M. Chem. Commun.
2003, 2476–2477. (b) Fernández de la Pradilla, R.; Buergo, M. V.; Manzano,
P.; Montero, C.; Priego, J.; Viso, A.; Cano, F. H.; Mart´ınez-Alca´zar, M. P. J.
Org. Chem. 2003, 68, 4797–4805. (c) Viso, A.; Fernández de la Pradilla, R.;
Garc´ıa, A.; Guerrero-Strachan, C.; Alonso, M.; Tortosa, M.; Flores, A.; Mart´ınez-
Ripoll, M.; Andre´, I. F. I.; Rodr´ıguez, A. Chem. Eur. J. 2003, 9, 2867–2876. (d)
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Flores, A.; Alonso, M. J. Org. Chem. 2004, 69, 1542–1547. (e) Fernández de la
Pradilla, R.; Montero, C.; Tortosa, M.; Viso, A. Chem. Eur. J. 2005, 11, 5136–
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M.; Lo´pez-Rodr´ıguez, M. L. J. Org. Chem. 2006, 71, 1442–1448.
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L. A. J. Org. Chem. 1998, 63, 9612–9613. (b) Fernández de la Pradilla, R.;
Viso, A. Recent Res. DeV. Org. Bioorg. Chem. 2001, 4, 123–132. (c) Fernández
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Mart´ınez-Cruz, L. A. J. Org. Chem. 2003, 68, 7755–7767. (d) Fernández de la
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de la Pradilla, R.; Fernández, J.; Viso, A.; Fernández, J.; Go´mez, A. Heterocycles
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J. Org. Chem. Vol. 73, No. 17, 2008 6717

Fernazndez de la Pradilla et al.
SCHEME 2. Synthesis of Iodo Vinyl Sulfoxides
obtained as single isomers using commercially available enan-
tiopure alkynols to prepare stannanes 7d.
Cyclization of Z,Z and E,Z Hydroxy Dienyl Sulfoxides.
Substrate 8b was selected as a representative example to pursue
the monoepoxidation to produce the desired vinyl oxirane related
to C (Scheme 1). After considerable experimentation, all
attempts of electrophilic epoxidation on hydroxy dienyl sul-
foxide 8b led to complex reaction mixtures or to the oxidation
of the sulfoxide to the sulfone. Therefore, we decided to examine
the base-induced cyclization of dienols 8 and 9 to obtain F-type
structures (Scheme 1). Table 1 summarizes the results obtained
for the cyclization of Z,Z dienols 8a-h to dihydropyrans F.
We first examined the use of 2 equiv of LDA with diene 8b, to
afford 2,3-trans dihydropyran 10b as a single isomer (Table 1,
entry 1). Even though the addition of the base was carried out
at low temperature, the product was not observed by TLC until
the temperature reached 0 °C. With diene 8a, under the same
conditions dihydropyran 10a was obtained, although a significant
amount of enyne 12, resulting from the base-promoted elimina-
tion of the sufinyl group, was obtained. Subsequently dihydro-
pyran 10a was obtained as a single isomer in excellent yield
decreasing the amount of base and again starting the reaction
at -78 °C (Table 1, entry 2). The use of NaH at low temperature
also afforded enantiopure 10a and 10b, with good yields (Table
1, entries 3 and 4). Interestingly, these allylic sulfoxides 10a,b
were stable and could be purified on silica gel and stored for
months, and no epimerization at sulfur was observed.
SCHEME 3. Synthesis of Hydroxy Dienyl Sulfoxides
The influence of an additional stereogenic center was explored
next under the optimized conditions. Diene 8e displayed a
similar behavior as the previous examples, affording allylic
sulfoxide 10e in good yield (Table 1, entry 5). Along with the
major product a small amount of vinyl sulfoxide was isolated,
resulting from the isomerization of the allylic double bond in
the final product. In contrast, diastereomeric dienol 8f did not
react under these conditions, and NaH was necessary to promote
cyclization (Table 1, entry 6). These results show that this
methodology gives straightforward access to enantiomerically
pure 2,6-cis and 2,6-trans dihydropyrans. The cyclization was
compatible with additional substitution on the diene. From diene
8g (R2 ) Me), using the original conditions (LDA, -78 °C to
rt), a 70:30 mixture of dihydropyran 10g and allylic alcohol
13g, resulting from sulfoxide-sulfenate sigmatropic rearrange-
ment of 10g, was obtained. As a consequence, we considered
that a hydride base would accelerate the cyclization and perhaps
suppress the rearrangement. Using KH, the yield of 10g was
optimized (Table 1, entry 7), and though the same conditions
were used for diene 8h, the product was obtained only in
moderate yield (Table 1, entry 8). Even though dihydropyrans
10f-h were obtained as single isomers, they were unstable on
silica gel or upon standing in CH2Cl2 solution. Epimerization
at sulfur was observed affording equilibrated mixtures of allylic
sulfoxides, 70:30 for 10f, and 50:50 for both 10g and 10h.
Scheme 4 shows the model proposed to rationalize the
formation of dihydropyrans 10 from Z,Z dienes 8 that assumes
an S-cis eclipsed conformation CdC/S-:13 and takes into
consideration the model proposed by Iwata for the addition of
oxygenated nucleophiles to cyclic vinyl sulfoxides under basic
conditions.8b,c Coordination of the sulfinyl oxygen and the
alkoxide with the metal would direct the attack to the R face of
the diene, forming an intermediate J that after protonation
process. The rapid tin-iodine exchange afforded E iodo vinyl
sulfoxides 5a and 5b from stannanes 3 and Z isomers 6a and
6b from intermediates 4.11
The iodo vinyl sulfoxides were then subjected to Stille
coupling conditions with a variety of known vinyl stannanes,
available in one step from commercially available alkynols.12
Thus, from E iodides 5a,b, and using vinyl stannanes 7a-e,
Z,Z hydroxy dienyl sulfoxides 8a-h were obtained (Scheme
3). In the case of Z iodo vinyl sulfoxides 6a,b, the Stille coupling
reaction was only carried out with stannane 7a, to afford Z,E
dienyl sulfoxides 9a,b. All dienyl sulfoxides were obtained with
moderate to excellent yields and were stable compounds.
Diastereomeric dienes 8e and 8f were prepared from racemic
stannane 7d (R1 ) Me, R2 ) H, n ) 0) and could be separated
by chromatography. It should be pointed out that they could be
(9) (a) Fernández de la Pradilla, R.; Tortosa, M. Org. Lett. 2004, 6, 2157–
2160. For recent reports of applications of this methodology, see: (b) Fernández
de la Pradilla, R.; Lwoff, N.; Viso, A. Tetrahedron Lett. 2007, 48, 8141–8144.
(c) Fernández de la Pradilla, R.; Lwoff, N. Tetrahedron Lett. 2008, 49, 4167–
4169.
(10) (a) Kosugi, H.; Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J.
Org. Chem. 1987, 52, 1078–1082. (b) Louis, C.; Mill, S.; Mancuso, V.; Hootele´,
C. Can. J. Chem. 1994, 72, 1347–1350.
(11) Paley, R. S.; de Dios, A.; Estroff, L. A.; Lafontaine, J. A.; Montero, C.;
McCulley, D. J.; Rubio, M. B.; Ventura, M. P.; Weers, H. L.; Fernández de la
Pradilla, R.; Castro, S.; Dorado, R.; Morente, M. J. Org. Chem. 1997, 62, 6326–
6343.
(12) (a) Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851–3854.
(b) Havra´nek, M.; Dvora´k, D. Synthesis 1998, 1264–1268. (c) Miura, K.; Wang,
D.; Matsumoto, Y.; Hosomi, A. Org. Lett. 2005, 7, 503–505.
(13) Tietze, L. F.; Schuffenhauer, A.; Schreiner, P. R. J. Am. Chem. Soc.
1998, 120, 7952–7958.
6718 J. Org. Chem. Vol. 73, No. 17, 2008

EnantioselectiVe Synthesis of Functionalized Dihydropyrans
TABLE 1. Base-Induced Cyclization of Z,Z Hydroxy Dienyl Sulfoxides
entry
R
R2
R1
8
conditions
10 (yield %)
1
2
3
4
5
6
7
8
9
n-Bu
Ph
Ph
n-Bu
Ph
Ph
Ph
n-Bu
n-Bu
H
H
H
H
H
H
Me
Me
H
H
H
H
H
8b
8a
8a
8b
8e
8f
8g
8h
8b
2 equiv LDA, -78 °C to rt, 4 h
1.1 equiv LDA, -78 °C to rt, 4 h
1.1 equiv NaH, -30 °C to rt, 20 h
1.3 equiv NaH, -30 °C to rt, 3 h
1.1 equiv LDA, -78 °C to rt, 2 h
1.3 equiv NaH, -30 °C to rt, 3 h
1.1 equiv KH, -30 °C to rt, 1 h 30 min
1.3 equiv KH, -30 °C to rt, 1 h 45 min
1.1 equiv DBU, 0 °C to rt, 5 days
10b (94)
10a (84)a
10a (72)
10b (82)
10e (70)b
10f (100)
10g (87)
10h (58)
10b (50)c
(S)-Me
(R)-Me
H
H
H
a
1H NMR of the crude reaction showed a 93:7 ratio of 10a and Z-12. b 17% of the corresponding vinyl sulfoxide was obtained. c 50% of 8b
recovered. Reaction carried out in CH2Cl2.
SCHEME 4. Rationalization of Cyclization Results
findings. From these results, it is tempting to speculate that,
with the strongly basic phosphazenes that allow for the use of
low temperatures and short times, the 2,3-cis dihydropyrans 11
might be the kinetic products, with the trans isomers 10 being
obtained under thermodynamic control by epimerization R to
sulfur. Alternatively, both isomers would arise from attack of
the alkoxide to the R face of the diene, leading to products with
the same configuration at C-2, identical to the findings for LDA
and hydrides. Subsequent protonation with inversion or retention
would afford the cis and trans products 11 and 10.15 The cis
alcohols 14 formed in the reaction would originate from the
facile sigmatropic rearrangement of the less stable 2,3-cis
sulfinyl dihydropyrans 11 under those conditions. The consider-
able complexity of these examples, leading to three products
in most cases precluded a more detailed study of the process,
particularly addressing the possibility of cis isomers 11 undergo-
ing epimerization to trans products 10.
At this stage, the cyclization of isomeric Z,E dienes 9a and
9b was explored, observing in both cases lower reactivities and
selectivities (Scheme 5). The use of LDA at low temperature
failed to promote the cyclization and the optimal conditions
required the use of KH for 9a and NaH for 9b. Treatment of
9a with KH provided a diastereomeric 2,3-trans product 16a
and a small amount of vinyl sulfoxide. In contrast, treatment
of 9b with NaH afforded 2,3-cis sulfinyl dihydropyran 15b and
a small amount of 10b with variable selectivities (from 96:4 to
68:12). Whereas 9b followed the stereochemical course previ-
ously observed for Z,Z dienes (attack to the R face and
protonation from the same face) to give 2,3-cis products, a
different scenario was found for 9a. We speculate that the
expected 2,3-cis product 15a could not be formed due to strong
steric interaction of the substituents in adjacent positions.
To broaden the scope of the methodology toward 7- and
8-membered oxacycles, we focused our attention on substrates
8c and 8d. While conditions previously successful for Z,Z
substrates (LDA, BEMP) led to recovery of starting material
for substrate 8c, the desired cyclic product 2,3-trans 17c was
obtained with hydride bases (Table 3, entries 1 and 2) as a single
isomer albeit in low yields. These yields were increased using
from the same face of the molecule, would lead to 2,3-trans
dihydropyran 10.
To generalize the process and study the effect of nonionic
bases on the stereochemistry of the cyclization, we examined
the use of other conditions. Initial experiments with substrate
8b using DBU in THF, afforded the expected product 10b with
very low yield, a result that could be slightly improved by
changing the solvent to CH2Cl2 and increasing the reaction time
(Table 1, entry 9).
We next examined phosphazene BEMP, in the same condi-
tions used for DBU, obtaining dihydropyran 10b with a
considerable amount of 3,6-cis alcohol 14b in good yield (Table
2, entry 1). When the stoichiometry of the base was decreased
and with shorter reaction times (Table 2, entry 2), a small
amount of 2,3-cis dihydropyran 11b was isolated accounting
for the rapid formation of 3,6-cis alcohol 14b. In the case of
substrate 8a, with an aromatic substituent, again both 2,3-trans
10a and 2,3-cis 11a isomers were isolated along with alcohol
14a (Table 2, entry 3).14
Seeking to improve the amount of 2,3-cis 11, we used a
stronger phosphazene base such as P2-tBu at -78 °C. These
new conditions increased the yield of cyclization for aromatic
substrate 8a (Table 2, entry 4) and reduced the amount of
alcohol 14a. In the case of 8b, shorter reaction times and a
nonaqueous workup, to prevent an eventual epimerization of
the 2,3-cis dihydropyran, gave a higher yield of isomer 11b,
along with some trans isomer 10b and a small amount of alcohol
14b (Table 2, entry 5). Finally, the use of P2-tBu or P4-tBu in
different solvents (toluene, CH2Cl2) did not improve the previous
(15) It should be mentioned that we made several attempts to trap the
intermediate anion formed in the reaction under different conditions (see
Supporting Information). Unfortunately, all efforts to capture the anion with MeI
were unsuccessful, but we were able to obtain dihydropyrans 10b and 11b
partially deuterated at C-3 with NaH and quenching with CD3OD.
(14) 2,3-cis and 2,3-trans stereochemistry was easily assigned by analysis
of coupling constants and NOESY-1D experiments (see Supporting Information).
J. Org. Chem. Vol. 73, No. 17, 2008 6719

Fernazndez de la Pradilla et al.
TABLE 2. Phosphazene-Induced Cyclization of Z,Z Hydroxy Dienyl Sulfoxides
entry
dienol
conditions
10a ratio %
11a ratio %
14a ratio %
combined yield %
1
2
3
4
5
8b
8b
8a
8a
8b
1.3 equiv BEMP, 0 °C to rt, 4 days
0.5 equiv BEMP, 0 °C to rt, 2 h
1.3 equiv BEMP, 0 °C to rt, 40 min
1.1 equiv P2-tBu, -78 °C, 1 h
10b (40)
10b (55)
10a (41)
10a (40)
10b (22)
14b (60)
14b (30)
14a (13)
14a (4)
100
61b
99
100
86
11b (15)
11a (46)
11a (56)
11b (58)
c
1.1 equiv P2-tBu, -78 °C, 5 min
14b (20)
a Ratio measured in 1H NMR of the crude product. b 37% of 8b recovered. c Nonaqueous workup. The cold reaction mixture was filtered through a
short pad of silica gel.
SCHEME 5. Base-Induced Cyclization of Z,E Hydroxy
Dienyl Sulfoxides
sulfones 20g and 20h, respectively. Finally, the oxidation of a
mixture of sulfoxides 17c and 18c led to a mixture of sulfones
22c and 23c with a similar ratio as the starting sulfoxide mixture.
At this stage we focused our efforts on carrying out
exploratory experiments on the reactivity of our sulfinyl
dihydropyrans to gain insight on the design of future synthetic
applications. We first examined the Pummerer rearrangement
of 10a that led to a complex reaction mixture. A hydroboration-
oxidation sequence was studied on the same substrate, and this
led to a mixture of regioisomers, along with a considerable
amount of sulfone products. The one-pot oxidation/epoxidation
of sulfinyl dihydropyrans 10a and 10b was explored using
m-CPBA under different conditions, but for both substrates, only
sulfones 20a,b were obtained. We briefly considered the
possibility of forming the desired epoxide from the correspond-
ing bromohydrin, but treatment of 10a with NBS led to a
complex mixture of unidentified products. The functionalization
of the carbon-carbon double bond by an osmium-catalyzed
dihydroxylation was considered a reasonable alternative, and
the results obtained are gathered in Table 5.17
a 10% of vinyl sulfoxide was obtained. b A ca. 1:1 mixture of 16a and
9a, 50% was isolated, along with ca. 50% of alcohole ent-13a.
phosphazene P2-tBu, but the product was obtained as a mixture
of trans-cis diastereoisomers 17c-18c (Table 3, entries 3 and
4). Unfortunately, none of the conditions examined for dienol
8d allowed for the formation of the eight-membered ring.
Reactivity and Chemical Correlations of Sulfinyl and
Sulfonyl Dihydropyrans. To study some aspects of the
reactivity of these allylic sulfoxides, we examined their behavior
under oxidation and dihydroxylation conditions and the results
are summarized in Tables 4 and 5 and Scheme 6. In addition,
a thorough study of the sigmatropic sulfoxide-sulfenate rear-
rangement was also carried out and the results of this study
will be described in due time.
The oxidation of several substrates under standard conditions
supports the stereochemical assignments carried out at the
sulfoxide stage. Substrates 10 and 11 afforded enantiopure allylic
sulfones 20 and 21,16 versatile synthetic intermediates, in good
yields (Table 4, Scheme 6). Thus, whereas 10a and 11a gave
diastereomeric allylic sulfones 20a and 21a, respectively (Table
4, entries 1 and 6), 10a and 16a led to enantiomeric products
(Scheme 6). Similarly, upon oxidation 11b and 15b afforded
21b and ent-21b, respectively. Furthermore, the oxidation of
diastereomeric mixtures of 10g and 10h gave single isomers of
The dihydroxylation of diastereomeric mixtures of sulfoxides
10g, substituted at position 4 and hence more conformationally
restricted substrates, gave an excellent yield of sulfonyl diol
24g (Table 5, entry 1). Encouraged by this result we examined
the dihydroxylation of less hindered substrates 10a,b that led
to good yield of diols 24a,b as single isomers. With substrate
10a we studied the reaction in depth trying to control the
overoxidation of the sulfoxide, but we were not able to obtain
the sulfinyl diol with good chemoselectivity (see Supporting
Information). The sulfinyl diol was oxidized with MMPP
affording the expected sulfonyl diol 24a as a single product,
which could also be obtained by dihydroxylation of sulfone 20a
(not shown, see Supporting Information). All attempts to carry
(17) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17,
1973–1976.
(18) All attempts to obtain the related sulfinyl diol using OsO4 under
controlled conditions led to mixtures of starting material, allylic sulfone, sulfinyl
diol, and sulfonyl diol 24. For details see Supporting Information.
(16) For reviews, see: (a) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107–
124. (b) Pyne, S. In StereoselectiVe Synthesis (Houben-Weyl); Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds; Thieme: Stuttgart, 1995;
Vol. E21b, p 2068.
6720 J. Org. Chem. Vol. 73, No. 17, 2008

EnantioselectiVe Synthesis of Functionalized Dihydropyrans
TABLE 3. Base-Induced Cyclizations to Obtain Seven-Membered Rings
entry
n
8
conditions
17:18 ratio
yield %
8c yield %
1
2
3
4
1
1
1
1
8c
8c
8c
8c
1.1 equiv NaH, THF, -30 °C to rt, 2 h 30 min
1.3 equiv KH, THF, -45 °C to rt, 3 h
17c:18c (100:0)
17c:18c (100:0)
17c:18c (81:19)
17c:18c (81:19)
29
26
47
65
59
39a
8a
1.1 equiv P2-tBu, CH2Cl2, -78 °C to rt, 2 h
1.1 equiv P2-tBu, CH2Cl2, -78 to -20 °C, 2 h
18
a 16% of diol 19c was recovered.
TABLE 4. Oxidation of Sulfinyl Dihydropyrans and
Stereochemical Correlations
SCHEME 6. Oxidation of Sulfinyl Dihydropyrans and
Stereochemical Correlations
entry 10/11
R
R1
R2
conditions
20/21 (yield %)
1
2
3
4
5
6
7
10a Ph
10b n-Bu
10f Ph
10g Ph
10h n-Bu
11a Ph
H
H
H
H
H
MMPP, MeOH
MMPP, MeOH
m-CPBA, CH2Cl2
20a (75)
20b (86)
20f (60)a
20g (68)b
20h (88)a
21a (61)
21b (31)c
(R)-Me
H
H
H
H
Me m-CPBA, CH2Cl2
Me MMPP, MeOH
H
H
m-CPBA, CH2Cl2
MMPP, MeOH
SCHEME 7. Reactivity of Hydroxy Sulfonyl Dihydropyrans
11b n-Bu
a Starting material [70:30] mixture of epimers at sulfur. b Starting
material [50:50] mixture of epimers at sulfur. c Allylic alcohol 14b
(58%) was also obtained. MMPP
phthalate) hexahydrate, m-CPBA ) m-chloroperbenzoic acid.
) magnesium bis(monoperoxy-
TABLE 5. Dihydroxylation of 2,3-trans Dihydropyrans 10
entry
10
R
R2
24 (yield %)
1
2
3
10g
10a
10b
Ph
Ph
n-Bu
Me
H
H
24g (86)a
24a (70)
24b (69)
a Starting material [50:50] mixture of epimers at sulfur.
out the desulfonylation of 24b failed, leading only to recovery
of the starting sulfonyl diol.19
were obtained with t-BuOONa, which led to epoxy sulfone 26
as a single isomer. The absolute configuration of hydroxy
sulfonyl oxirane 26 was determined by synthesis of (S)- and
(R)-methoxyphenylacetates 28 and 29 (Scheme 7).22
Sulfonyl oxirane 26 could be cleaved with MgBr2 to obtain
bromopyranone 30 (Scheme 8), initially as a single isomer,
Sulfonyl diol 24a was transformed smoothly to hydroxy vinyl
sulfone 25 (Scheme 7), structurally related to our initial objective
D (Scheme 1), according to the protocol of Rayner.20 Next, the
nucleophilic epoxidation of hydroxy vinyl sulfone 25 using
metallated hydroperoxides was explored, and optimal results
(19) (a) Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547–10658. (b) Lee,
G. H.; Youn, I. K.; Choi, E. B.; Lee, H. K.; Yon, G. H.; Yang, H. C.; Pak, C. S.
Curr. Org. Chem. 2004, 8, 1263–1287. (c) Das, I.; Pathak, T. Org. Lett. 2006,
8, 1303–1306.
(20) Westwell, A. D.; Thornton-Pett, M.; Rayner, C. M. J. Chem. Soc. Perkin
Trans. 1 1995, 847–859.
(21) Briggs, A. D.; Jackson, R. F. W.; Brown, P. A. J. Chem. Soc., Perkin
Trans. 1 1998, 4097–4102.
(22) (a) For details see Supporting Information. (b) Latypov, S. K.; Seco,
J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1996, 61, 8569–8577. For a review
on the determination of absolute configuration by NMR, see: (c) Seco, J. M.;
Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17–118.
J. Org. Chem. Vol. 73, No. 17, 2008 6721

Fernazndez de la Pradilla et al.
SCHEME 8. Reactivity of Hydroxy Sulfonyl Oxirane 26
SCHEME 9. Synthesis of Hydroxy Dienyl Sulfoximines
which underwent a rapid epimerization of the halogen bearing
center.23 An attempt to cleave the C-Br bond with Al-Hg led
to an equimolar mixture of the desired product 31 and diol 32
derived from dehalogenation and concurrent ring cleavage.
Treatment of the mixture with Bu3SnH and AIBN resulted not
only in the elimination of the bromine atom but also in a rapid
and stereoselective reduction of the carbonyl group, obtaining
diol 33 as a single isomer in excellent yield (Scheme 8).
At this stage we wanted to explore the reactivity of our
dihydropyranyl allylic sulfones 20 and 21 in copper-mediated
SN2′ processes. While this study was successful in some cases
(see below), some important limitations prompted us to consider
that the use of the related dihydropyranyl allylic sulfoximines
could display an enhanced reactivity in those processes and,
additionally, the chiral leaving group might influence the
stereochemical outcome of the displacement.24 Furthermore,
examining the behavior of hydroxy dienyl sulfoximines related
to our sulfinyl dienols E (Scheme 1) in this chemistry was
considered to be an interesting extension of the methodology.
Therefore we set out to explore briefly the preparation of
hydroxy dienyl sulfoximines using similar chemistry to that used
for the related sulfoxides.
Preparation of Hydroxy Dienyl Sulfoximines. Imination
of sulfoxide 2b as described by Malacria25 led to alkynyl
sulfoximine 34, which was transformed into stannanes E-35 and
Z-36 by hydrostannylation (Scheme 9). Interestingly, while the
uncatalyzed hydrostannylation was completely selective and
high-yielding, the Pd-catalyzed variant afforded an equimolar
mixture of stannanes 35 and 36. The behavior of stannane 36
as a coupling partner in the Stille reaction with iodobenzene
was tested, to afford the expected product in moderate yield
along with the product of protonolysis, 39. It should be noted
that this coupling is somewhat more efficient than when the
related sulfinyl stannane is used. Alternatively, stannane 36 was
smoothly transformed into vinyl iodide 37 that was coupled with
hydroxy vinyl stannane 7a in a Stille process to afford Z,E diene
40 in low yield. Since tin-halogen exchange of stannane 35
was low-yielding, we essayed the imination of readily available
hydroxy sulfinyl diene 8b to obtain Z,Z diene 41 in moderate
yield. It should be mentioned that we have assumed that all of
these iminations take place with complete retention of config-
uration at the sulfur atom, in analogy with the findings of
Malacria.25
Cyclization of Hydroxy Dienyl Sulfoximines. The cycliza-
tion of hydroxy sulfoximinoyl dienes 40 and 41 was then briefly
examined in a parallel fashion as the related sulfoxides, and
the results are shown in Table 6. Dienyl sulfoximine 41 gave
dihydropyrans 42 and 43 in similar yields and selectivity with
LDA or KH (Table 6, entries 1 and 2), whereas the use of NaH
led to comparable selectivity but with lower yield. Because of
availability problems with dienol 40, we were able to try only
the conditions with NaH, to obtain an equimolar mixture of
allylic sulfoximines 42 and 43 that were difficult to separate
by chromatography.
In analogy to the results obtained for sulfoxides, we expected
that 42 and 43 would arise by alkoxide attack to the same face
of the diene and protonation from opposite faces to form both
trans and cis diastereoisomers, as we had previously observed
at least in one case. The NOESY experiments for 42 and 43
were not conclusive, and therefore to confirm the stereochem-
istry initially assigned to these allylic sulfoximines, we explored
the imination of the related sulfinyl dihydropyrans (Scheme 10).
Since these allylic sulfoxides were perceived as potentially
sensitive substrates, the behavior of substrate 10b with each of
the reagents for the imination was examined separately, and no
epimerization or diastereomerization at sulfur was observed. The
imination of 10b led to 2,3-trans 42 that was identical to the
minor product obtained in the cyclization of 41. We then
expected to obtain 43 from the imination of cis diastereoisomer
11b, and surprisingly we obtained a new isomer 2,3-cis 44.
Similarly, the imination of the alternative cis isomer 15b led to
45, and again we were surprised to discover it had spectroscopic
properties different from those of 43. Therefore, we concluded
that the only remaining possibility was that the absolute
stereochemistry of 43 was a 2,3-trans system diastereomeric to
42. The patterns found for the chemical shifts of 44 and 45
(23) (a) de Reinach-Hirtzbach, F.; Durst, T. Tetrahedron Lett. 1976, 17, 3677–
3680. (b) Mori, Y.; Hayashi, H. Tetrahedron 2002, 58, 1789–1797.
(24) (a) Gais, H.-J.; Mueller, H.; Bund, J.; Scommoda, M.; Brandt, J.; Raabe,
G. J. Am. Chem. Soc. 1995, 117, 2453–2466. (b) Scommoda, M.; Gais, H.-J.;
Bosshammer, S.; Raabe, G. J. Org. Chem. 1996, 61, 4379–4390. (c) Reggelin,
M.; Zur, C. Synthesis 2000, 1–64.
(25) (a) Lacoˆte, E.; Amatore, M.; Fensterbank, L.; Malacria, M. Synlett 2002,
116–118. (b) Leca, D.; Song, K.; Amatore, M.; Fensterbank, L.; Lacoˆte, E.;
Malacria, M. Chem. Eur. J. 2004, 10, 906–916.
6722 J. Org. Chem. Vol. 73, No. 17, 2008

EnantioselectiVe Synthesis of Functionalized Dihydropyrans
TABLE 6. Cyclization of Dienyl Sulfoximines
entry
substrate
conditions
42:43 ratio
yield %
1
2
3
4
41
41
41
40
1.1 equiv LDA THF, -78 °C to rt, 3 h
1.3 equiv KH THF, -78 °C to rt, 1 h 30 min
1.3 equiv NaH THF, -78 °C to rt, 1 h 30 min
2.6 equiv NaH THF, -78 °C, 5 h
20:80
15:85
17:83
50:50
68
68
54
79
SCHEME 10. Imination of Sulfinyl Dihydropyrans
The rationalization of results for Z,E isomer 40 would imply
a less restricted conformation about the C-S bond that results
in a nonselective attack of the alkoxide to the dienyl sulfoximine,
producing an equimolar mixture of 42 and 43. Though dienyl
sulfoximines display a higher reactivity than the related sul-
foxides, their selectivity in these processes is much lower, at
least in the few examples examined; these results underline the
synthetic usefulness of the sulfinyl functionality for this
chemistry. Nonetheless, it should be pointed out that, after
optimization of the cyclization of dienyl sulfoximines, in
principle, both enantiomeric series of dihydropyrans could be
accessed from the same precursor by adjusting the oxidation
state at sulfur.
SN2′ Displacements of Allylic Sulfones and Sulfoximines.
To explore the reactivity of our dihydropyranyl allylic sulfones,
their behavior under different SN2′ displacement conditions was
examined. When necessary, 3-tosylcyclohexene was used as a
model substrate before trying the different processes on sulfone
20b. The Lewis acid promoted reaction with silyl enol ethers
was successfully carried out with AlCl3, affording the expected
ketone for the model system.16a Unfortunately substrate 20b
did not react with any of the Lewis acids tried (EtAlCl2, AlCl3,
BF3 ·Et2O, TiCl4). Allylation of 20b with a variety of Lewis
acids and allyl trimethylsilane was unsuccessful. Free radical
processes with Bu3SnH and AIBN afforded complex reaction
mixtures, where small amounts of substitution products could
be identified, but they could not be isolated cleanly. Several
attempts of palladium-catalyzed substitution with malonate anion
also failed to afford substituted products, leading to the recovery
of sulfone 20b. At this stage we focused our efforts on the SN2′
reaction of allylic sulfoxides, sulfones, and sulfoximines with
organocuprates. The displacement on allylic sulfoxide 10b (not
shown) afforded only traces of the desired product, and mainly
starting material was recovered. In contrast allylic sulfones
displayed a reasonable, albeit somewhat capricious behavior and
these results are gathered in Table 7. As expected, these
displacements led to products of regioselective γ attack of the
cuprate to the allylic sulfone.27
SCHEME 11. Rationalization of Cyclization Results for
Dienyl Sulfoximine 41
were similar, in agreement with their cis relative configuration,
enantiomeric except for the configuration at sulfur.
We believe the stereochemical outcome of this cyclization
is the result of the low facial selectivity in the attack of the
alkoxide intermediate to the diene and protonation from the same
face of the attack in both cases. This could be caused by the
different conformation adopted by the substrates to accom-
modate the chiral sulfoximine group to minimize possible
interactions.26 A tentative rationalization implies an anti ar-
rangement of the N-tosyl group relative to the vinyl group, which
places the oxygen atom above the plane of the diene, and attack
of the nucleophile could be controlled by coordination of the
alkoxide to the sulfoximine oxygen (Scheme 11). This alkoxide
attack is also occurring on the less-hindered face of the diene.
Thus, for dienol 41 a relatively weak coordination of the
alkoxide with the sulfoximine oxygen from the less hindered ꢀ
face would lead to a metallated allylic sulfoximine K that after
protonation from the ꢀ face would deliver 43.
At the beginning, we carried out a small scale reaction of
2,3-trans 20b and n-Bu2CuLi to produce a good yield of 3,6-
cis 46a. However, the use of n-butyllithium to generate the
cuprate gave results difficult to reproduce, and when the scale
was increased, Z,E sulfonyl diene 47, presumably derived from
ring cleavage of 20b, was obtained as the major product (Table
7, entries 1 and 2). The Z,E stereochemistry of 47 was confirmed
(27) (a) Julia, M.; Righini-Tapif, A.; Verpeaux, J.-N. Tetrahedron 1983, 39,
3283–3287. (b) Julia, M.; Verpeaux, J.-N. Tetrahedron 1983, 39, 3289–3291.
(c) Masaki, Y.; Sakuma, K.; Kaji, K. J. Chem. Soc., Perkin Trans. 1 1985, 1171–
1175. (d) Ba¨ckvall, J. E.; Juntunen, S. K. J. Am. Chem. Soc. 1987, 109, 6396–
6403.
(26) (a) Jackson, R. F. W.; Briggs, A. D.; Brown, P. A.; Clegg, W.; Elsegood,
M. R. J.; Frampton, C. J. Chem. Soc., Perkin Trans. 1 1996, 1673–1682. (b)
Briggs, A. D.; Clegg, W.; Elsegood, M. R. J.; Frampton, C. S.; Jackson, R. F. W.
Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1998, 54, 1335–1341.
J. Org. Chem. Vol. 73, No. 17, 2008 6723

Fernazndez de la Pradilla et al.
TABLE 7. SN2′ on Dihydropyranyl Allylic Sulfones with
Organocuprates
TABLE 8. SN2′ on Dihydropyranyl Allylic Sulfoximines with
Organocuprates
entry sulfone
R′
conditionsa
46/48 (yield %) SM %
entry
R′
substrate
conditionsa
46/ent-48 (yield %) SM %
1
2
3
4
5
6
7
20b
20b
20b
20b
20b
20b
21a
n-Bu n-Bu2CuLi
n-Bu n-Bu2CuLi
n-Bu n-Bu2CuMgBr
allyl
Me
Ph
46a (78)b
46a (46)c
1
2
3
4
5
n-Bu
n-Bu
allyl
Me
42
42
42
42
43
n-Bu2CuLi
46a 46a(46)
46a(70)
53
12
26
n-Bu2CuMgBr
allyl2CuMgBr
Me2CuMgBr
n-Bu2CuMgBr
46a (66)
46b (24)d
46c (52)e
46d (93)
48e (37)
34
47
6
46b(20)b
allyl2CuMgBr
Me2CuMgBr
Ph2CuMgBr
46c(55)
n-Bu
ent-48a(44)c
n-Bu n-Bu2CuLi
a All reactions were carried out in Et2O-THF as solvent, from 0 °C
to rt. b Small scale, product could not be isolated. Brominated
byproducts were the major products. c 29% of brominated byproduct
was isolated.
a All reactions were carried out in Et2O-THF as solvent, from 0 °C
to rt. b 0.078 mmol scale. c Z,E Sulfonyl diene 47 was isolated as the
major product. d 0.08 mmol scale, estimated yield; product could not be
isolated. e 42% of 47 was isolated.
ment of 2,3-cis sulfone 21a (Table 7, entry 7) with the lithium
cuprate gave a low yield of 3,6-trans disubstituted dihydropyran
48e.
SCHEME 12. Reactivity of Hydroxymethyl Dienyl Sulfones
In an effort to overcome the limitations of these displacements
and to compare the reactivity of both functionalities, the behavior
of the related allylic sulfoximines was explored. It has been
reported that allylic sulfoximines react with organocuprates with
high selectivity at the R-position and with organocopper reagents
in the presence of boron trifluoride and lithium iodide with an
equally high selectivity at the γ-position. We thought that our
cyclic allylic sulfoximines provided an opportunity to expand
the scope of this study.24a,b
Surprisingly, the SN2′ displacement of 2,3-trans sulfoximine
42 gave similar results as the corresponding sulfone 2,3-trans
20b, both with lithium and magnesium as counterions of the
organocuprate species (Table 8, entries 1 and 2), with again
the Grignard derived reagent leading to optimal results. Dihy-
dropyran 46a had identical spectroscopic data and optical
rotation to the one derived from the reaction of sulfone 20b.
Allyl and methyl nucleophiles gave yields similar to those
obtained for sulfone 20b, (Table 8, entries 3 and 4), and we
again found difficulties isolating the allylated product, obtaining
brominated derivatives as major products (not shown). In the
case of 2,3-trans diastereoisomer 43 we expected ent-46 to be
the major displacement product, since the starting material
presented opposite configuration from 42 except for the sulfur
atom. Surprisingly, we obtained 3,6-trans product ent-48a,
(Table 8, entry 5) as the major product along with brominated
derivatives (not shown).
by comparison with the isomeric dienyl sulfone Z,Z 49,
generated by oxidation (MMPP) of the known Z,Z dienyl
sulfoxide 8b (Scheme 12). The cyclization of sulfonyl diene
47 with NaH was examined, to render racemic 2,3-trans 20b
as a single diastereoisomer. It should be noted that Z,E dienyl
sulfone 47 and dienyl sulfoximine 40 afford 2,3-trans dihydro-
pyrans, albeit with different selectivities; this is in sharp contrast
with Z,E dienyl sulfoxide 9b that yields mainly 2,3-cis
dihydropyrans.
Seeking to avoid the formation of 47, different sources of
copper and counterions were studied (Table 7). Copper salts
different from CuI did not produce any substitution product,
probably because of the low reactivity of the organocuprates
and the high stability of the allylic sulfone. Alternatively
Grignard-derived organocuprate reagents presented a more
reproducible behavior, affording similar yields of substituted
product 46a as the lithium cuprates (Table 7, entry 3). The use
of an organocopper reagent and the reaction with the vinyl
cuprate led only to recovery of starting material. Allyl and
methyl derivatives 46b and 46c could be obtained with low to
moderate yields (Table 7, entries 4 and 5), but when the cuprate
was formed from MeMgI sulfonyl diene 47 was again the main
product of the reaction. In contrast, an aromatic residue was
introduced in excellent yield to produce 46d (Table 7, entry 6),
giving access to interesting cores for synthetic targets, perhaps
by oxidation of the aryl group into a carboxylic acid, thus
increasing the scope of the methodology.28 Finally, the displace-
These results suggest that the sulfoximine group in the starting
material is influencing the conformation of the ring thus directing
the attack of the cuprate onto the allylic center. In the case of
vinyl sulfoximines it has been reported that different cations
and organometallic species have a profound effect on the
asymmetric conjugate addition of copper reagents.26a,30 Assum-
ing a similar behavior for allylic derivatives, we believe that
attack of the cuprate to 42 could occur anti as expected due
(29) Brominated by-products could be formed by SN2′ substitution of
sulfoximine moiety by bromide present in the reaction media resulting in a
diastereomeric mixture of brominated derivatives (see Supporting Information).
(30) Pyne, S. G. Tetrahedron Lett. 1986, 27, 1691–1694.
(28) Nagumo, S.; Ishii, Y.; Kakimoto, Y.-I.; Kawahara, N. Tetrahedron Lett.
2002, 43, 5333–5337.
6724 J. Org. Chem. Vol. 73, No. 17, 2008

EnantioselectiVe Synthesis of Functionalized Dihydropyrans
SCHEME 13. Dihydroxylation and Epoxidation of
Disubstituted Dihydropyrans
0.2 equiv), and Pd2(dba)3 ·CHCl3 (42 mg, 0.04 mmol, 0.05 equiv),
according to the general procedure described in Supporting
Information (12 h), diene 8a was obtained as a single isomer.
Purification by chromatography (5-80% EtOAc-hexane) afforded
229 mg of 8a as a brown solid. A second purification (10-50%
EtOAc-CH2Cl2) afforded 8a (200 mg, 0.67 mmol, 83%) as a pale
brown solid that was recrystallized from EtOAc-hexane. Rf 0.14
(50% EtOAc-hexane). Mp 135-137 °C. [R]20 -162.2 (c 1.00).
D
1H NMR (300 MHz) δ 2.38 (s, 3 H), 2.67 (br s, 1 H), 3.97 (dddd,
1 H, J ) 12.7, 8.3, 6.1, 0.7 Hz), 4.18 (dddd, 1 H, J ) 12.7, 8.1,
4.7, 1.2 Hz), 5.76 (ddd, 1 H, J ) 11.2, 2.8, 1.1 Hz), 6.12 (ddd, 1
H, J ) 11.2, 8.3, 6.1 Hz), 6.98 (d, 1 H, J ) 1.5 Hz), 7.26 (d, 2 H,
J ) 8.1 Hz), 7.36-7.46 (m, 5 H), 7.52-7.57 (m, 2 H). 13C NMR
(75 MHz) δ 21.4, 58.3, 121.8, 124.5 (2 C), 128.6 (2 C), 129.1,
129.8 (4 C), 133.6, 138.1, 138.2, 139.1, 141.2, 141.8. IR (KBr):
3401, 3021, 1630, 1490, 1445, 1318, 1230, 1183, 1079, 1042, 1017,
1003, 806, 759, 700 cm-1. MS (ES): 619 [2M + Na]+, 321 [M +
Na]+, 299 [M + 1]+ (100%). Anal. Calcd for C18H18O2S: C, 72.45;
H, 6.08; S, 10.75. Found: C, 72.24; H, 6.12; S, 10.70.
(-)-(2S,3R,RS)-2-Phenyl-3-(p-tolylsulfinyl)-3,6-dihydro-2H-py-
ran (10a). From dienyl sulfoxide 8a (597 mg, 2 mmol) and LDA
(4.4 mL, 2.2 mmol) according to the general procedure (Supporting
Information, method A, 4 h), dihydropyran 10a was obtained.
Chromatography (15-50% EtOAc-hexane) afforded 12 (35 mg,
0.11 mmol, 5%) as a colorless oil and 10a (500 mg, 1.67 mmol,
84%) as a white solid that was recrystallized from hexane.
mainly to steric reasons to produce 46. In contrast, the
conformation of 43 may favor coordination of the sulfoximine
to the organocuprate species and this could direct the attack to
obtain the syn SN2′ product ent-48a.
Finally we have carried out preliminary studies on the
reactivity of the SN2′ products obtained from allylic sulfones
and sulfoximines, exploring the dihydroxylation and epoxidation
of dihydropyrans 46a and 46d (Scheme 13). The dihydroxylation
with OsO4/Me3NO occurred with complete stereoselectivity on
the ꢀ face for both substrates to afford cis diols 50a and 50d,
respectively, in good yields, as expected for a 3,6-cis disubsti-
tuted dihydropyran.31 The stereochemical assignment was further
confirmed by analysis of the coupling constants (1H NMR) of
diacetate 51a, generated by acetylation of 50a. Finally, epoxi-
dation of 46a with m-CPBA gave a mixture of diastereoisomers
52 and 53 in good yield and with negligible selectivity. These
transformations outline new possibilities of synthetic applica-
tions for dihydropyranyl allylic sulfones and sulfoximines by
exploiting their reactivity in SN2′ processes.
Data for 10a: Rf 0.34 (50% EtOAc-hexane). Mp 87-89 °C.
1
[R]20 -291.7 (c 0.82). H NMR (300 MHz), COSY δ 2.44 (s, 3
D
H, Me-p-Tol), 3.78 (m, 1 H, H-3), 3.91 (dq, 1 H, J ) 17.6, 2.4 Hz,
H-6), 4.14 (dm, 1 H, J ) 17.6 Hz, H-6), 5.33 (d, 1 H, J ) 2.9 Hz,
H-2), 5.51 (ddtd, 1 H, J ) 10.2, 4.9, 2.2, 0.5 Hz, H-4), 6.00 (dtd,
1 H, J ) 10.2, 3.2, 1.0 Hz, H-5), 7.30-7.40 (m, 7 H), 7.59 (d, 2
H, J ) 8.3 Hz). NOESY-1D H-2/p-Tol: 0.6%; H-2/Ph: 1.9%; H-2/
H-3: 1.0%; H-3/H-2: 1.3%; H-3/H-4: 1.6%; H-3/p-Tol: 1.3%; H-3/
Ph: 3.2%; H-4/H-5: 2.2%; H-4/p-Tol: 1.1%; H-4/H-3: 1.5%; H-5/
H-4: 1.3%; H-5/H-6%: 1.1%; H-5/H-6 (4.14 ppm): 1.1%; H-5/H-6
(3.91 ppm): 1.9%; H-6/H-5: 2.1%. 13C NMR (75 MHz), HSQC δ
21.5 (Me-p-Tol), 61.6 (C-6), 64.3 (C-3), 71.5 (C-2), 117.1 (C-4),
125.6 (2 C), 127.9 (2 C), 128.3, 128.5 (2 C), 129.7 (2 C), 133.2
(C-5), 137.3, 138.4, 142.2. IR (KBr): 2945, 2829, 1632, 1490, 1449,
Conclusion
The base-promoted intramolecular cyclization of 2-sulfinyl
dienols to obtain enantiopure sulfinyl dihydropyrans has been
studied in depth. This strategy allows for creation of two
asymmetric centers within a synthetically useful dihydropyran
framework in an expedient manner.32 This methodology is
amenable to the preparation of seven-membered rings, albeit
in low to moderate yields. The reactivity of our sulfinyl
dihydropyrans toward oxidation, imination, and dihydroxylation
has been explored. In this manner several routes to densely
functionalized pyran derivatives have been outlined. Finally,
we have examined the SN2′ displacements of allylic sulfonyl
and sulfoximinoyl dihydropyrans with organocuprate reagents,
to obtain 3,6-disubstituted dihydropyrans, potentially useful for
the preparation of attractive synthetic targets.33
1304, 1198, 1074, 1041, 1015, 960, 897, 821, 807, 752, 700 cm-1
.
MS (ES): 619 [2M + Na]+, 321 [M + Na]+, 299 [M + 1]+ (100%).
Anal. Calcd for C18H18O2S: C, 72.45; H, 6.08; S, 10.75. Found: C,
72.60; H, 6.26; S, 10.38.
Data for 12: Rf 0.45 (50% EtOAc-hexane). 1H NMR (300 MHz)
δ 1.61 (br s, 1 H), 4.49 (t, 2 H, J ) 4.6 Hz), 5.80 (dt, 1 H, J )
11.0, 1.5 Hz), 6.13 (dt, 1 H, J ) 11.0, 6.3 Hz), 7.28-7.32 (m, 3
H), 7.40-7.43 (m, 2 H). MS (ES): 159 [M + 1]+ (100%), 141
[(M - 18) + 1]+.
(+)-(2S,3S,RS)-2-Phenyl-3-(p-tolylsulfinyl)-3,6-dihydro-2H-py-
ran (11a). From dienyl sulfoxide 8a (40 mg, 0.134 mmol) and
BEMP (1.3 equiv, 51 µL, 0.174 mmol) according to the general
procedure (Supporting Information, method D, 40 min) a 46:41:13
mixture of 11a, 10a, and 14a was obtained. Purification by
chromatography (0-20% EtOAc-CH2Cl2) afforded 11a (17 mg,
0.056 mmol, 41%) as a white solid and a 75:25 mixture of 10a
Experimental Section
and 14a (18 mg) as a colorless oil. Rf 0.27 (30% EtOAc-CH2Cl2).
(-)-(S)-2-(Z)-4-(Z)-5-Phenyl-4-(p-tolylsulfinyl)penta-2,4-dien-
1-ol (8a). From iodide 5a (295 mg, 0.80 mmol, 1.0 equiv), a 62:38
mixture of (Z)-3-(tributylstannyl)prop-2-en-1-ol, 7a, and 2-(tribu-
tylstannyl)prop-2-en-1-ol, 7a′ (1.09 g, 3.14 mmol, 1.5 equiv of 7a),
BHT (176 mg, 0.80 mmol, 1.0 equiv), Ph3As (50 mg, 0.16 mmol,
1
Mp 108-110 °C. [R]20 +566.0 (c 0.70). H NMR (400 MHz),
D
COSY δ 2.35 (s, 3 H, CH3 p-Tol), 3.33 (ap dt, 1 H, J ) 5.7, 2.7
Hz, H-3), 4.40 (dq, 1 H, J ) 17.4, 2.4 Hz, H-6), 4.62 (dt, 1 H, J
) 17.2, 2.6 Hz, H-6), 5.07 (d, 1 H, J ) 2.9 Hz, H-2), 5.50 (ddt, 1
H, J ) 8.0, 5.8, 2.8 Hz, H-4), 6.34 (m, 1 H, H-5), 7.15 (d, 2 H, J
) 8.2 Hz, Hm p-Tol), 7.19 (d, 2 H, J ) 8.4 Hz, Ho p-Tol), 7.35 (d,
1 H, J ) 7.1 Hz, Hp Ph), 7.42 (t, 2 H, J ) 7.5 Hz, Hm Ph), 7.50 (d,
2 H, J ) 7.5 Hz, Ho Ph). NOESY-1D H-2/H-6 (4.40 ppm): 2.7%;
H-2/H-3: 6.5%; H-2/Ph: 3.3%. 13C NMR (100 MHz), HSQC δ 21.4
(Me p-Tol), 66.7 (C-3), 66.9 (C-6), 76.4 (C-2), 116.3 (C-4), 123.9
(2 C, Ar), 126.1 (2 C Ar), 128.0 (Ar-C), 128.6 (2 C Ar), 129.6 (2
C Ar), 134.7 (C-5), 138.7, 140.4, 140.6. IR (KBr): 3435, 3028,
(31) Kozikowski, A. P.; Schmiesing, R. J.; Sorgi, K. L. J. Am. Chem. Soc.
1980, 102, 6577–6580.
(32) Enantiopure propargyl alcohols, precursors to the required substituted
stannanes are readily available. See: El-Sayed, E.; Anand, N. K.; Carreira, E. M.
Org. Lett. 2001, 3, 3017–3020. This suggests that our methodology should be
broadly applicable.
(33) For a review on the synthesis of Pseudomonic acids, see: Class, Y. J.;
DeShong, P. Chem. ReV. 1995, 95, 1843–1857.
J. Org. Chem. Vol. 73, No. 17, 2008 6725

Fernazndez de la Pradilla et al.
2921, 2833, 1635, 1490, 1452, 1183, 1101, 1049, 805, 752, 727,
705, 670 cm-1. MS (ES): 619 [2M + Na]+ (100%), 321 [M +
Na]+, 299 [M + 1]+.
(-)-(S)-[(Z)-1-(S-p-Tolyl-N-tosylsulfoximinoyl)hex-1-enyl]tribu-
tylstannane (36). To a solution of 34 (144 mg, 0.37 mmol) in 2
mL of hexane-toluene (2:1) (5 mL/mmol sulfoximine) at room
temperature under argon was added a solution of freshly distilled
Bu3SnH (0.11 mL, 0.407 mmol, 1.1 equiv), in 1 mL of hexane (3
mL/mmol sulfoximine). The mixture was stirred at room temper-
ature for 21 h, and the solvent was evaporated to obtain 36.
Purification by chromatography (5-30% EtOAc-hexane) afforded
stannane 36 (226 mg, 0.332 mmol, 90%) as a colorless oil. Rf 0.20
(20% EtOAc-hexane). [R]20D -41.2 (c 1.20). 1H NMR (300 MHz)
δ 0.82 (t, 9 H, J ) 7.2 Hz), 0.87 (t, 3 H, J ) 7.1 Hz), 0.98 (m, 2
H), 1.16-1.38 (m, 20 H), 2.17 (q, 2 H, J ) 7.5 Hz), 2.35 (s, 3 H),
2.41 (s, 3 H), 7.01 (t, 1 H, J ) 7.5 Hz), 7.17 (d, 2 H, J ) 8.1 Hz),
7.28 (d, 2 H, J ) 8.5 Hz), 7.70 (d, 2 H, J ) 8.3 Hz), 7.76 (d, 2 H,
J ) 8.3 Hz). 13C NMR (75 MHz) δ 12.6 (3 C), 13.6 (3 C), 21.4,
21.6, 22.5, 27.0 (4 C), 28.6 (3 C), 30.8, 33.3, 126.7 (2 C), 128.5 (2
C), 128.9 (2 C), 129.7 (2 C), 135.7, 141.5, 142.0, 144.2, 145.7,
156.4. IR (film): 2957, 2926, 2867, 1595, 1522, 1456, 1367, 1318,
1236, 1154, 1089, 1064, 1015, 813, 744, 668 cm-1. MS (ES): 704
[M + Na]+, 682 [M + 1]+.
(+)-(R)-2-(Z)-4-(Z)-4-(S-p-Tolyl-N-tosylsulfoximinoyl)nona-2,4-
dien-1-ol (41). From dienyl sulfoxide 8b (27 mg, 0.097 mmol),
N-tosyl phenyliminoiodinane (47 mg, 0.126 mmol, 1.3 equiv) and
Cu(OTf)2 (4 mg, 0.010 mmol, 0.10 equiv), according to the general
procedure described in Supporting Information (5 min), sulfoximine
41 was obtained. Purification by chromatography (0-10%
EtOAc-CH2Cl2) afforded dienyl sulfoximine 41 (26 mg, 0.058
mmol, 60%) as a colorless oil. Rf 0.14 (10% EtOAc-CH2Cl2).
[R]20D +73.6 (c 0.92). 1H NMR (300 MHz), COSY δ 0.86 (t, 3 H,
J ) 7.1 Hz, CH3), 1.23-1.43 (m, 4 H, 2 CH2), 2.36 (s, 3 H, Me-
p-Tol), 2.41 (s, 3 H, Me-Ts), 2.65-2.74 (m, 2 H, CH2), 3.99 (dd,
1 H, J ) 13.4, 3.4 Hz, H-1), 4.26 (dd, 1 H, J ) 13.4, 3.9 Hz, H-1),
5.98 (ap t, 2 H, J ) 4.0 Hz, H-2, H-3), 6.08 (t, 1 H, J ) 7.7 Hz,
H-5), 7.23 (d, 2 H, J ) 8.3 Hz, Ar-H), 7.32 (d, 2 H, J ) 8.3 Hz,
Ar-H), 7.82 (d, 2 H, J ) 8.3 Hz, Ar-H), 7.85 (d, 2 H, J ) 8.3 Hz,
Ar-H). 13C NMR (75 MHz), HSQC δ 13.8 (CH3-Bu), 21.5 (Me),
21.6 (Me), 22.4 (CH2), 28.2 (CH2), 31.0 (CH2), 58.4 (C-1), 124.3,
126.5 (2 C), 127.9 (2 C), 129.2 (2 C), 129.9 (2 C), 135.2, 135.6,
137.4, 141.0, 142.7, 145.4, 148.5 (C-5). IR (film): 3499, 2956, 2928,
2867, 1735, 1596, 1454, 1316, 1303, 1233, 1153, 1088, 1065, 1013,
814 cm-1. MS (ES): 917 [2M + Na]+, 470 [M + Na]+ (100%),
448 [M + 1]+.
(+)-(2R,3S,RS)-2-Phenyl-3-(p-tolylsulfinyl)-3,6-dihydro-2H-py-
ran (16a). From dienyl sulfoxide 9a (30 mg, 0.100 mmol) and KH
(5.2 mg, 0.130 mmol, 1.3 equiv) according to the general procedure
(Supporting Information, method B, 2 h), an 85:15 mixture of 16a
and 16a′ was obtained. Purification by chromatography (20-50%
EtOAc-hexane) afforded 16a (20 mg, 0.067 mmol, 67%) and 16a′
impure with traces of 10a (3 mg, 0.010 mmol, 10%) as colorless
oils.
Data for 16a: Rf 0.29 (50% EtOAc-hexane). [R]20 +248.2 (c
D
0.50). 1H NMR (300 MHz), COSY δ 2.37 (s, 3 H, Me-p-Tol), 3.45
(ap dquint, 1 H, J ) 8.3, 2.7 Hz, H-3), 4.19 (ddd, 1 H, J ) 17.1,
5.6, 2.5 Hz, H-6), 4.32 (ddd, 1 H, J ) 17.1, 5.5, 2.3 Hz, H-6), 4.90
(d, 1 H, J ) 8.5 Hz, H-2), 5.59 (dq, 1 H, J ) 10.5, 2.3 Hz, H-4),
6.20 (ddt, 1 H, J ) 10.5, 3.4, 2.1 Hz, H-5), 7.26-7.45 (m, 7 H),
7.50 (dm, 2 H, J ) 8.3 Hz). NOESY-1D H-2/p-Tol: 2.3%; H-3/
H-4: 2.3%; H-3/p-Tol: 1.8%; H-3/Ph: 2%; H-6/H-5: 5.7%; H-6/
H-5: 2%; H-6/H-2: 2.9%. 13C NMR (75 MHz), HSQC δ 21.4 (Me-
p-Tol), 65.3 (C-6), 65.7 (C-3), 75.7 (C-2), 117.3 (C-4), 124.3 (2
C), 127.6 (2 C), 128.8 (3 C), 129.8 (2 C), 134.2 (C-5), 137.6, 138.8,
141.2. IR (film): 3028, 2923, 2855, 1596, 1492, 1453, 1177, 1084,
1045, 910, 809, 757 cm-1. MS (ES): 619 [2M + Na]+ (100%),
321 [M + Na]+, 299 [M + 1]+.
1
Partial data for 16a′: Rf 0.16 (10% EtOAc-CH2Cl2). H NMR
(300 MHz) δ 2.33 (s, 3 H), 2.45 (m, 2 H), 3.67 (ddd, 1 H, J )
11.6, 6.3, 5.1 Hz), 3.87 (dt, 1 H, J ) 11.7, 5.6 Hz), 5.20 (ap dd, 1
H, J ) 3.9, 2.2 Hz), 6.85 (ddd, 1 H, J ) 4.6, 3.4, 1.5 Hz), 7.08-7.22
(m, 9 H).
(-)-(2S,3R)-2-n-Butyl-3-(p-tolylsulfonyl)-3,6-dihydro-2H-py-
ran (20b). From sulfoxide 10b (569 mg, 2.04 mmol) and MMPP
[1.9 g (80%), 3.06 mmol], according to the general procedure
described in Supporting Information (3 h) sulfone 20b was obtained.
Purification by chromatography (10-30% EtOAc-hexane) afforded
20b (517 mg, 1.76 mmol, 86%) as a colorless oil. Rf 0.38 (30%
1
EtOAc-hexane). [R]20 -150.6 (c 0.59). H NMR (300 MHz) δ
D
0.87 (t, 3 H, J ) 7.1 Hz), 1.20-1.40 (m, 4 H), 1.62 (m, 2 H), 2.42
(s, 3 H), 3.51 (m, 1 H), 3.63 (ddd, 1 H, J ) 17.6, 4.6, 2.4 Hz),
3.93 (ddd, 1 H, J ) 17.6, 4.8, 2.7 Hz), 4.13 (ddd, 1 H, J ) 8.7,
5.4, 3.7 Hz), 5.87 (ddt, 1 H, J ) 10.2, 3.7, 2.2 Hz), 6.00 (dtd, 1 H,
J ) 10.2, 2.7, 1.5 Hz), 7.30 (d, 2 H, J ) 8.1 Hz), 7.71 (d, 2 H, J
) 8.3 Hz). 13C NMR (75 MHz) δ 14.0, 21.7, 22.4, 27.6, 32.0, 60.8,
64.6, 70.8, 117.0, 129.3, 129.6, 133.0, 134.1, 144.6. IR (film): 3022,
2949, 2928, 2859, 1597, 1493, 1456, 1380, 1309, 1301, 1284, 1216,
1182, 1132, 1084, 1019, 814, 758, 708 cm-1. MS (ES): 611 [2M
+ Na]+, 317 [M + Na]+, 295 [M + 1]+ (100%).
(-)-(2S,3R,RS)-2-n-Butyl-3-(S-p-tolyl-N-tosylsulfoximinoyl)-3,6-
dihydro-2H-pyran (42) and (+)-(2R,3S,RS)-2-n-Butyl-3-(S-p-tolyl-
N-tosylsulfoximinoyl)-3,6-dihydro-2H-pyran (43). From dienyl
sulfoximine 41 (24 mg, 0.054 mmol) and NaH (2 mg, 0.07 mmol,
1.3 equiv) according to the general procedure (Supporting Informa-
tion, method B, 1 h 30 min), an 83:17 mixture of 43 and 42 was
obtained. Purification by chromatography (10-30% EtOAc-hexane)
afforded an 83:17 mixture of 43 and 42 (13 mg, 0.029 mmol, 54%)
as a colorless oil. Subsequent chromatographies (30-50%
Et2O-hexane) allowed for the separation and characterization of
both isomers.
(+)-(3S,4S,5R,6S)-6-Phenyl-5-(p-tolylsulfonyl)tetrahydro-2H-py-
ran-3,4-diol (24a). From sulfoxide 10a (90 mg, 0.300 mmol),
Me3NO (133 mg, 1.200 mmol) and OsO4 [0.19 mL (2.5%), 0.015
mmol], according to the general procedure described in Supporting
Information (1 day), diol 24a was obtained. Purification by
chromatography (30-80% EtOAc-hexane) afforded 24a (74 mg,
0.21 mmol, 70%) as a white solid that was recrystallized from
EtOAc-hexane. Rf 0.32 (80% EtOAc-hexane). Mp 133-135 °C.
[R]20D +35.0 (c 0.48). 1H NMR (300 MHz), COSY δ 2.29 (s, 3 H,
Me-p-Tol), 2.88 (s, 1 H, OH), 3.71 (dm, 1 H, J ) 12.7 Hz, H-2),
3.93 (t, 1 H, J ) 10.1 Hz, H-5), 4.08 (m, 1 H, H-3), 4.14 (dd, 1 H,
J ) 12.7, 2.2 Hz, H-2), 4.45 (d, 1 H, J ) 10.0 Hz, H-6), 4.57
(ddd, 1 H, J ) 10.2, 3.4, 1.6 Hz, H-4), 5.15 (dd, 1 H, J ) 1.5, 0.5
Hz, OH), 6.92 (d, 2 H, J ) 8.5 Hz), 6.98-7.12 (m, 7 H). 13C NMR
(75 MHz), HSQC δ 21.5 (Me-p-Tol), 67.3 (C-3), 67.6 (C-5), 67.9
(C-4), 69.5 (C-6), 78.7 (C-2), 127.4 (2 C), 128.2 (2 C), 128.8 (2
C), 129.2 (2 C), 136.1, 136.2, 144.1. IR (KBr): 3503, 3065, 2913,
Data for 42: Rf 0.26 (50% EtOAc-hexane). Mp 89-91 °C.
1
[R]20 -142.5 (c 0.71). H NMR (300 MHz) δ 0.87 (t, 3 H, J )
D
7.1 Hz), 1.24-1.36 (m, 4 H), 1.37-1.68 (m, 2 H), 2.36 (s, 3 H),
2.40 (s, 3 H), 3.38 (d, 1 H, J ) 18.1 Hz), 3.84 (ddd, 1 H, J ) 18.1,
4.9, 2.0 Hz), 4.43 (m, 1 H), 4.48 (dd, 1 H, J ) 9.8, 4.8 Hz), 5.94
(ddd, 1 H, J ) 10.3, 2.1, 1.0 Hz), 6.02 (d, 1 H, J ) 10.5 Hz), 7.23
(d, 2 H, J ) 8.3 Hz), 7.28 (d, 2 H, J ) 8.1 Hz), 7.76 (d, 2 H, J )
1
8.5 Hz), 7.86 (d, 2 H, J ) 8.5 Hz). H NMR (300 MHz, C6D6) δ
0.84 (t, 3 H, J ) 7.2 Hz), 1.19-1.39 (m, 4 H), 1.40-1.56 (m, 2
H), 1.80 (s, 3 H), 1.82 (s, 3 H), 2.97 (dt, 1 H, J ) 17.8, 2.2 Hz),
3.34 (dq, 1 H, J ) 18.1, 2.4 Hz), 4.66 (hept, 1 H, J ) 1.5 Hz),
4.83 (ap t, 1 H, J ) 7.1 Hz), 5.27 (dq, 1 H, J ) 10.2, 1.5 Hz), 5.77
(dddd, 1 H, J ) 10.3, 5.4, 3.2, 1.0 Hz), 6.74 (d, 2 H, J ) 9.7 Hz),
6.77 (d, 2 H, J ) 7.8 Hz), 7.85 (d, 2 H, J ) 8.3 Hz), 8.28 (d, 2 H,
J ) 8.3 Hz). 13C NMR (75 MHz) δ 13.9, 21.5, 21.7, 22.3, 27.6,
30.6, 59.2, 65.8, 70.1, 115.1, 126.6 (2 C), 129.2 (4 C), 130.0 (2
2876, 1627, 1595, 1288, 1230, 1138, 1097, 882, 813, 768, 724 cm-1
.
MS (ES): 719 [2M + Na]+ (100%), 371 [M + Na]+, 349 [M +
1]+. Anal. Calcd for C18H20O5S: C, 62.05; H, 5.79; S, 9.20. Found:
C, 62.36; H, 5.47; S, 9.31.
6726 J. Org. Chem. Vol. 73, No. 17, 2008

EnantioselectiVe Synthesis of Functionalized Dihydropyrans
C), 130.8, 134.8, 141.1, 142.6, 145.4. IR (film): 2950, 2926, 2867,
butylmagnesium bromide (0.68 mL, 0.81 M, 0.552 mmol, prepared
form magnesium turnings and n-BuBr in Et2O), according to the
general procedure described in Supporting Information (21 h),
dihydropyran 46a was obtained. Purification by chromatography
(2-5%-EtOAc-hexane) afforded 46a (12 mg, 0.061 mmol, 66%)
as a colorless oil, along with recovered starting material (9 mg,
1594, 1451, 1316, 1152, 1088, 1062, 1015, 940, 812, 753 cm-1
.
MS (ES): 917 [2M + Na]+ (100%), 470 [M + Na]+. Anal. Calcd
for C23H29NO4S2: C, 61.72; H, 6.53; N, 3.13; S, 14.33. Found: C,
61.53; H, 6.40; N, 3.20; S, 14.24.
Data for 43: Rf 0.26 (50% EtOAc-hexane). [R]20 +146.0 (c
D
1
0.031 mmol, 34%). Rf 0.48 (10% EtOAc-hexane). [R]20 -11.1
0.86). H NMR (300 MHz, C6D6) δ 0.75 (t, 3 H, J ) 7.0 Hz),
D
1
1.05-1.78 (m, 6 H), 1.80 (s, 3 H), 1.81 (s, 3 H), 2.87 (ddd, 1 H,
J ) 17.8, 3.2, 2.1 Hz), 3.27 (ddd, 1 H, J ) 17.9, 5.1, 2.1 Hz), 4.45
(ddd, 1 H, J ) 9.5, 4.2, 2.0 Hz), 4.69 (ap td, 1 H, J ) 3.3, 1.5 Hz),
5.28 (d, 1 H, J ) 10.3 Hz), 6.20 (dddd, 1 H, J ) 10.3, 5.4, 3.2, 1.0
Hz), 6.74 (d, 2 H, J ) 8.1 Hz), 6.77 (d, 2 H, J ) 8.1 Hz), 7.84 (d,
2 H, J ) 8.3 Hz), 8.30 (d, 2 H, J ) 8.3 Hz). NOESY-1D H-2/H-3:
3%; H-2/CH2 (Bu): 3%; H-2/Ar-H: 2%; H-3/Bu: 1.4%; H-3/H-4:
1.4%; H-6 (3.27 ppm)/H-5: 5%, H-6 (3.27 ppm)/CH2 (Bu): 2%;
H-6 (2.87 ppm)/H-5: 2.4%; H-6 (2.87 ppm)/H-3: 0.4%. 13C NMR
(75 MHz, CDCl3), HSQC δ 13.9 (CH3-Bu), 21.5 (Me-p-Tol), 21.7
(Me-Ts), 22.3 (CH2), 27.7 (CH2), 31.0 (CH2), 59.3 (CH2), 65.9 (C-
3), 69.2 (C-2), 116.2 (C-4), 126.6 (2 C), 129.2 (4 C), 129.9 (2 C),
130.8, 134.4 (C-5), 140.8, 142.8, 145.3. IR (film): 3392, 2956, 2929,
2867, 1596, 1454, 1316, 1237, 1152, 1088, 1065, 1016, 814, 753,
704 cm-1. MS (ES): 917 [2M + Na]+ (100%), 470 [M + Na]+.
(+)-(2S,3S,RS)-2-n-Butyl-3-(S-p-tolyl-N-tosylsulfoximinoyl)-3,6-
dihydro-2H-pyran (44). From dihydropyran 11b (13 mg, 0.047
mmol), N-tosyl phenyliminoiodinane (21 mg, 0.056 mmol) and
Cu(OTf)2 (4 mg, 0.01 mmol), according to the general procedure
described in Supporting Information (30 min), sulfoximine 44 was
obtained. Purification by chromatography (10-30% EtOAc-hexane)
afforded sulfoximine 44 (11 mg, 0.025 mmol, 53%) as a white
solid that was recrystallized from CH2Cl2-hexane. Rf 0.24 (30%
(c 0.75). H NMR (500 MHz), COSY δ 0.88 (t, 3 H, J ) 7.1 Hz,
CH3), 0.88 (t, 3 H, J ) 7.2 Hz, CH3), 1.21-1.52 (m, 12 H, 6 CH2),
1.92 (m, 1 H, H-3), 3.67 (ap d, 2 H, J ) 3.9 Hz, H-2), 4.02 (hept,
1 H, J ) 2.5 Hz, H-6), 5.59 (dt, 1 H, J ) 10.3, 1.7 Hz, H-5), 5.78
(ddd, 1 H, J ) 10.3, 4.5, 2.1 Hz, H-4). 13C NMR (125 MHz), HSQC
δ 14.0 (CH3), 14.1 (CH3), 22.8 (CH2), 22.9 (CH2), 27.4 (CH2), 29.4
(CH2), 33.1 (CH2), 34.8 (CH2), 34.9 (C-3), 67.2 (C-2), 74.1 (C-6),
129.3 (C-5), 129.7 (C-4). IR (film): 2962, 2920, 2850, 1650, 1459,
1376, 1261, 1091, 1020, 800 cm-1. MS (ES): 219 [M + Na]+, 197
[M + 1]+.
(-)-(2S,3R,4R,5R)-2,5-Di-n-butyltetrahydro-2H-pyran-3,4-diol
(50a). From dihydropyran 46a (25 mg, 0.127 mmol), Me3NO (36
mg, 0.318 mmol), and OsO4 [75 µL (2.5%), 0.006 mmol], according
to the general procedure described in Supporting Information (1 h
40 min), diol 50a was obtained. Purification by chromatography
(0-20% EtOAc-CH2Cl2) afforded 50a (24 mg, 0.104 mmol, 82%)
as a white solid. Rf 0.35 (20% EtOAc-CH2Cl2). Mp 57-59 °C.
[R]20D -2.8 (c 1.23). 1H NMR (300 MHz), COSY δ 0.87 (t, 3 H,
J ) 6.9 Hz, CH3), 0.88 (t, 3 H, J ) 7.0 Hz, CH3), 1.23-1.51 (m,
12 H, 6 CH2), 1.65-1.72 (m, 1 H, H-5), 2.10 (br s, 2 H, 2 OH),
3.45 (m, 2 H, H-2, H-4), 3.50 (dd, 1 H, J ) 11.8, 2.5 Hz, H-6),
3.77 (dd, 1 H, J ) 11.7, 3.2 Hz, H-6), 3.81 (t, 1 H, J ) 2.7 Hz,
H-3). 13C NMR (75 MHz) δ 14.0 (2 C), 22.8 (2 C), 27.7, 28.5,
29.8, 31.2, 41.8, 64.6, 69.6, 71.3, 76.6. IR (KBr): 3339, 2958, 2926,
2857, 1465, 1291, 1262, 1082, 1020, 801, 760 cm-1. MS (ES):
253 [M + Na]+, 198 [M+2-2OH]+ (100%). Anal. Calcd for
C13H26O3: C, 67.79; H, 11.38. Found: C, 67.72; H, 11.21.
EtOAc-hexane). Mp 102-104 °C. [R]20 +131.6 (c 1.12). H
1
D
NMR (300 MHz, C6D6), COSY δ 0.87 (t, 3 H, J ) 6.9 Hz, CH3),
1.17-1.46 (m, 4 H, 2 CH2), 1.79 (s, 3 H, Me-p-Tol), 1.81 (s, 3 H,
Me-Ts), 1.90-2.06 (m, 2 H, CH2), 3.06 (d, 1 H, J ) 17.3 Hz,
H-6), 3.24 (ddd, 1 H, J ) 8.3, 5.4, 3.0 Hz, H-2), 3.36 (dd, 1 H, J
) 17.6, 2.2 Hz, H-6), 4.91 (ap q, 1 H, J ) 2.7 Hz, H-3), 5.29 (dd,
1 H, J ) 10.2, 1.1 Hz, H-5), 6.38 (ddt, 1 H, J ) 10.2, 5.7, 2.2 Hz,
H-4), 6.69 (d, 2 H, J ) 8.5 Hz, Ar-H), 6.77 (dd, 2 H, J ) 8.0, 0.6
Hz, Ar-H), 7.81 (d, 2 H, J ) 8.3 Hz, Ar-H), 8.29 (d, 2 H, J ) 8.3
Hz, Ar-H). 13C NMR (75 MHz, C6D6) δ 14.2, 21.0, 21.1, 22.8,
29.2, 32.7, 66.0, 66.1, 75.7, 120.7, 127.2 (2 C), 129.0 (2 C), 129.3
(2 C), 130.4 (2 C), 133.5, 134.0, 142.0, 142.8, 144.4. IR (KBr):
2956, 2927, 2855, 1597, 1313, 1228, 1200, 1155, 1088, 1058, 1014,
812, 751, 686, 659 cm-1. MS (ES): 917 [2M + Na]+ (100%), 470
[M + Na]+. Anal. Calcd for C23H29NO4S2: C, 61.72; H, 6.53; N,
3.13; S, 14.33. Found: C, 62.01; H, 6.39; N, 3.09; S, 14.51.
(-)-(3R,6R)-3,6-Di-n-butyl-3,6-dihydro-2H-pyran (46a). From
sulfone 20b (27 mg, 0.092 mmol), CuI (54 mg, 0.276 mmol), and
Acknowledgment. This research was supported by DGI MEC
(CTQ2006-04522/BQU) and CM (S-SAL-0249-2006). We
thank JANSSEN-CILAG for generous additional support and
MEC for doctoral fellowships to NL, MT and MAA.
Supporting Information Available: Experimental details and
spectral data (1H NMR and 13C NMR) for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801029Q
J. Org. Chem. Vol. 73, No. 17, 2008 6727